Publications by authors named "Rong-fu Wang"

131 Publications

BECN2 (beclin 2) Negatively Regulates Inflammasome Sensors Through ATG9A-Dependent but ATG16L1- and LC3-Independent Non-Canonical Autophagy.

Autophagy 2021 Jun 21:1-17. Epub 2021 Jun 21.

Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX, USA.

Macroautophagy/autophagy-related proteins regulate infectious and inflammatory diseases in autophagy-dependent or -independent manner. However, the role of a newly identified mammalian-specific autophagy protein-BECN2 (beclin 2) in innate immune regulation is largely unknown. Here we showed that loss of BECN2 enhanced the activities of NLRP3, AIM2, NLRP1, and NLRC4 inflammasomes upon ligand stimulations. Mechanistically, BECN2 interacted with inflammasome sensors and mediated their degradation through a ULK1- and ATG9A-dependent, but BECN1-WIPI2-ATG16L1-LC3-independent, non-canonical autophagic pathway. BECN2 recruited inflammasome sensors on ATG9A vesicles to form a complex (BECN2-ATG9A-sensors) upon ULK1 activation. Three soluble NSF attachment protein receptor (SNARE) proteins (SEC22A, STX5, and STX6) were further shown to mediate the BECN2-ATG9A-dependent inflammasome sensor degradation. Loss of BECN2 promoted alum-induced peritonitis, which could be rescued by the ablation of CASP1 in -deficient mice. Hence, BECN2 negatively regulated inflammasome activation to control inflammation, serving as a potential therapeutic target for the treatment of infectious and inflammatory diseases.: AIM2: absent in melanoma 2; ATG: autophagy related; BECN1: beclin 1; BMDC: bone marrow-derived dendritic cells; BMDM: bone marrow-derived macrophages; CASP1: caspase 1; CQ: chloroquine; gMDSC: granulocytic myeloid-derived suppressor cells; IL: interleukin; LPS: lipopolysaccharide; MAP1LC3B: microtubule associated protein 1 light chain 3 beta; mMDSC: monocytic myeloid-derived suppressor cells; NLRC4: NLR family CARD domain containing 4; NLRP1: NLR family pyrin domain containing 1; NLRP3: NLR family pyrin domain containing 3; PECs: peritoneal exudate cells; PYCARD/ASC: apoptosis-associated speck-like protein containing a caspase activation and recruitment domain; SNAREs: soluble NSF attachment protein receptors; STX5: syntaxin 5; STX6: syntaxin 6; ULK1: unc-51 like autophagy activating kinase 1; WIPI: WD repeat domain, phosphoinositide interacting.
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http://dx.doi.org/10.1080/15548627.2021.1934270DOI Listing
June 2021

Microbiota regulate innate immune signaling and protective immunity against cancer.

Cell Host Microbe 2021 06 23;29(6):959-974.e7. Epub 2021 Apr 23.

Department of Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA; Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA; Department of Pediatrics, Children's Hospital Los Angeles, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90027, USA; Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX 77030, USA. Electronic address:

Microbiota play critical roles in regulating colitis and colorectal cancer (CRC). However, it is unclear how the microbiota generate protective immunity against these disease states. Here, we find that loss of the innate and adaptive immune signaling molecule, TAK1, in myeloid cells (Tak1) yields complete resistance to chemical-induced colitis and CRC through microbiome alterations that drive protective immunity. Tak1 mice exhibit altered microbiota that are critical for resistance, with antibiotic-mediated disruption ablating protection and Tak1 microbiota transfer conferring protection against colitis or CRC. The altered microbiota of Tak1 mice promote IL-1β and IL-6 signaling pathways, which are required for induction of protective intestinal Th17 cells and resistance. Specifically, Odoribacter splanchnicus is abundant in Tak1 mice and sufficient to induce intestinal Th17 cell development and confer resistance against colitis and CRC in wild-type mice. These findings identify specific microbiota strains and immune mechanisms that protect against colitis and CRC.
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http://dx.doi.org/10.1016/j.chom.2021.03.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8192480PMC
June 2021

BECN2 (beclin 2)-mediated non-canonical autophagy in innate immune signaling and tumor development.

Autophagy 2020 12 29;16(12):2310-2312. Epub 2020 Oct 29.

Department of Medicine, And Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California , Los Angeles, CA, USA.

BECN2 (beclin 2) is a newly identified mammalian-specific macroautophagy/autophagy family member, and plays a critical role in the control of obesity and insulin sensitivity. However, its role in innate immune signaling and inflammation remains elusive. In our recent study, we show that BECN2 functions as a negative regulator in innate immune signaling and tumor development through non-canonical autophagy. Loss of causes splenomegaly, lymphadenopathy, elevated proinflammatory cytokine production and spontaneous lymphoma development in mice. Mechanistically, BECN2 mediates the degradation of MAP3K7/TAK1 and MAP3K3/MEKK3 through an ATG9A- and ULK1-dependent but ATG16L1-BECN1-MAP1LC3B/LC3B-independent autophagy pathway to control systemic inflammation. BECN2 interacts with MAP3K7 and MAP3K3 through the engagement of ATG9A vesicles upon ULK1 activation, and promotes the fusion of MAP3K3- or MAP3K7-associated ATG9A vesicles with phagophores for subsequent degradation. Our findings have identified a previously unrecognized role of BECN2 in innate immune signaling and tumor development through non-canonical autophagy, thus providing a potential target for inflammatory disease and cancer therapy.
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http://dx.doi.org/10.1080/15548627.2020.1839277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7751501PMC
December 2020

PHF20 Promotes Glioblastoma Cell Malignancies Through a /-Dependent Pathway.

Front Oncol 2020 6;10:573318. Epub 2020 Oct 6.

Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX, United States.

Glioblastoma (GBM) stem cells are resistant to cancer therapy, and therefore responsible for tumor progression and recurrence after conventional therapy. However, the molecular mechanisms driving the maintenance of stemness and dedifferentiation are poorly understood. In this study, we identified plant homeodomain finger-containing protein 20 (PHF20) as a crucial epigenetic regulator for sustaining the stem cell-like phenotype of GBM. It is highly expressed in GBM and tightly associated with high levels of aggressiveness of tumors and potential poor prognosis in GBM patients. Knockout of PHF20 inhibits GBM cell proliferation, as well as its invasiveness and stem cell-like traits. Mechanistically, PHF20 interacts with WDR5 and binds to the promoter regions of WISP1 for its expression. Subsequently, WISP1 and BGN act in concert to regulate the degradation of β-Catenin. Our findings have identified PHF20 as a key driver of GBM malignant behaviors, and provided a potential target for developing prognosis and therapy.
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http://dx.doi.org/10.3389/fonc.2020.573318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7574681PMC
October 2020

Donafenib in Progressive Locally Advanced or Metastatic Radioactive Iodine-Refractory Differentiated Thyroid Cancer: Results of a Randomized, Multicenter Phase II Trial.

Thyroid 2021 04 15;31(4):607-615. Epub 2020 Oct 15.

Department of Nuclear Medicine, Zhejiang Cancer Hospital, Hangzhou, China.

An unmet need for more effective and affordable kinase inhibitors remains in patients with progressive radioactive iodine-refractory differentiated thyroid cancer (RAIR-DTC) in China, where only sorafenib is approved for this indication. This study evaluated the 24-week objective response rate (ORR) to donafenib-a new, domestic multikinase inhibitor-in the treatment of locally advanced or metastatic RAIR-DTC in patients with measurable lesions. Two dose regimens (300 mg twice daily vs. 200 mg twice daily) were used to determine its optimal dosage and safety for further phase III studies. This study was a randomized, open-label, multicenter phase II trial. Thirty-five adult RAIR-DTC patients with at least one measurable targeted lesion according to RECIST 1.1 were enrolled from 12 centers in China and randomized to receive either 200 mg (17 patients) or 300 mg (18 patients) of donafenib orally twice daily for 24 weeks. The primary endpoint was ORR, and the secondary endpoints included progression-free survival (PFS) among others. Additionally, biochemical (serum thyroglobulin) and structural (total tumor diameter [TTD]) responses were assessed, change (ΔTTD) rates were calculated, and safety was evaluated. The ORRs for the 200- and 300-mg arms were 12.5% and 13.33% ( = 1.000), respectively. The 300-mg arm had a nonsignificant, longer median PFS than the 200-mg arm (14.98 months vs. 9.44 months) ( = 0.351). There was a trend toward more tumor shrinkage in the 300-mg arm compared with the 200-mg arm (average ΔTTD rate -0.52 ± 0.71 vs. -0.04 ± 1.55 mm/month,  = 0.103). Most treatment-related adverse events (AEs) in both arms were grades 1-2. The most common grade 3 treatment-related AEs in both arms were palmar-plantar erythrodysesthesia and hypertension; the sum occurrence rates of these two AEs in the 200-mg and 300-mg arms were 11.43% and 22.86%, respectively. Donafenib was generally well tolerated. Both donafenib regimens demonstrated similar efficacy in terms of the ORR in locally advanced or metastatic RAIR-DTC. The results warrant further studies on donafenib as a new, feasible treatment option for RAIR-DTC patients. Clinical Trials.gov IDs: NCT02870569; CTR20160220.
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http://dx.doi.org/10.1089/thy.2020.0235DOI Listing
April 2021

Beclin 2 negatively regulates innate immune signaling and tumor development.

J Clin Invest 2020 10;130(10):5349-5369

Department of Medicine and.

Beclin 2 plays a critical role in metabolic regulation and obesity, but its functions in innate immune signaling and cancer development remain largely unknown. Here, we identified Beclin 2 as a critical negative regulator of inflammation and lymphoma development. Mice with homozygous ablation of BCL2-interacting protein 2 (Becn2) developed splenomegaly and lymphadenopathy and markedly increased ERK1/2 and NF-κB signaling for proinflammatory cytokine production. Beclin 2 targeted the key signaling kinases MEKK3 and TAK1 for degradation through an ATG9A-dependent, but ATG16L/Beclin 1/LC3-independent, autophagic pathway. Mechanistically, Beclin 2 recruited MEKK3 or TAK1 through ATG9A to form a complex (Beclin 2-ATG9A-MEKK3) on ATG9A+ vesicles upon ULK1 activation. Beclin 2 further interacted with STX5 and STX6 to promote the fusion of MEKK3- or TAK1-associated ATG9A+ vesicles to phagophores for subsequent degradation. Importantly, Becn2-deficient mice had a markedly increased incidence of lymphoma development, with persistent STAT3 activation. Myeloid-specific ablation of MEKK3 (Map3k3) completely rescued the phenotypes (splenomegaly, higher amounts of proinflammatory cytokines, and cancer incidence) of Becn2-deficient mice. Hence, our findings have identified an important role of Beclin 2 in the negative regulation of innate immune signaling and tumor development through an ATG9A-dependent, but ATG16L/Beclin 1/LC3-independent, autophagic pathway, thus providing a potential target for the treatment of inflammatory diseases and cancer.
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http://dx.doi.org/10.1172/JCI133283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524487PMC
October 2020

The E3 ubiquitin ligase MARCH1 regulates antimalaria immunity through interferon signaling and T cell activation.

Proc Natl Acad Sci U S A 2020 07 30;117(28):16567-16578. Epub 2020 Jun 30.

Malaria Functional Genomics Section, Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892-8132;

Malaria infection induces complex and diverse immune responses. To elucidate the mechanisms underlying host-parasite interaction, we performed a genetic screen during early (24 h) infection in mice and identified a large number of interacting host and parasite genes/loci after transspecies expression quantitative trait locus (Ts-eQTL) analysis. We next investigated a host E3 ubiquitin ligase gene () that was clustered with interferon (IFN)-stimulated genes (ISGs) based on the similarity of the genome-wide pattern of logarithm of the odds (LOD) scores (GPLS). inhibits MAVS/STING/TRIF-induced type I IFN (IFN-I) signaling in vitro and in vivo. However, in malaria-infected hosts, deficiency of reduces IFN-I production by activating inhibitors such as SOCS1, USP18, and TRIM24 and by altering immune cell populations. deficiency increases CD86DC (dendritic cell) populations and levels of IFN-γ and interleukin 10 (IL-10) at day 4 post infection, leading to improved host survival. T cell depletion reduces IFN-γ level and reverse the protective effects of deficiency, which can also be achieved by antibody neutralization of IFN-γ. This study reveals functions of MARCH1 (membrane-associated ring-CH-type finger 1) in innate immune responses and provides potential avenues for activating antimalaria immunity and enhancing vaccine efficacy.
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http://dx.doi.org/10.1073/pnas.2004332117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7368286PMC
July 2020

Evaluation of Single-Cell Cytokine Secretion and Cell-Cell Interactions with a Hierarchical Loading Microwell Chip.

Cell Rep 2020 04;31(4):107574

Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX 77030, USA; Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, NY 10065, USA. Electronic address:

Comprehensive evaluation of single T cell functions such as cytokine secretion and cytolysis of target cells is greatly needed in adoptive cell therapy (ACT) but has never been fully fulfilled by current approaches. Herein, we develop a hierarchical loading microwell chip (HL-Chip) that aligns multiple cells and functionalized beads in a high-throughput microwell array with single-cell/bead precision based on size differences. We demonstrate the potential of the HL-Chip in evaluating single T cell functions by three applications: high-throughput longitudinal secretory profiling of single T cells, large-scale evaluation of cytolytic activity of single T cells, and integrated T cell-tumor cell interactions. The HL-Chip is a simple and robust technology that constructs arrays of defined cell/object combinations for multiple measurements and material retrieval.
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http://dx.doi.org/10.1016/j.celrep.2020.107574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583657PMC
April 2020

Cell-Penetrating Nanoparticles Activate the Inflammasome to Enhance Antibody Production by Targeting Microtubule-Associated Protein 1-Light Chain 3 for Degradation.

ACS Nano 2020 03 20;14(3):3703-3717. Epub 2020 Feb 20.

Department of Medicine, and Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, United States.

Engineered nanoparticles could trigger inflammatory responses and potentiate a desired innate immune response for efficient immunotherapy. Here we report size-dependent activation of innate immune signaling pathways by gold (Au) nanoparticles. The ultrasmall-size (<10 nm) Au nanoparticles preferentially activate the NLRP3 inflammasome for Caspase-1 maturation and interleukin-1β production, while the larger-size Au nanoparticles (>10 nm) trigger the NF-κB signaling pathway. Ultrasmall (4.5 nm) Au nanoparticles (Au4.5) activate the NLRP3 inflammasome through directly penetrating into cell cytoplasm to promote robust ROS production and target autophagy protein-LC3 (microtubule-associated protein 1-light chain 3) for proteasomal degradation in an endocytic/phagocytic-independent manner. LC3-dependent autophagy is required for inhibiting NLRP3 inflammasome activation and plays a critical role in the negative control of inflammasome activation. Au4.5 nanoparticles promote the degradation of LC3, thus relieving the LC3-mediated inhibition of the NLRP3 inflammasome. Finally, we show that Au4.5 nanoparticles could function as vaccine adjuvants to markedly enhance ovalbumin (OVA)-specific antibody production in an NLRP3-dependent pattern. Our findings have provided molecular insights into size-dependent innate immune signaling activation by cell-penetrating nanoparticles and identified LC3 as a potential regulatory target for efficient immunotherapy.
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http://dx.doi.org/10.1021/acsnano.0c00962DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7457719PMC
March 2020

Myeloid loss of Beclin 1 promotes PD-L1hi precursor B cell lymphoma development.

J Clin Invest 2019 12;129(12):5261-5277

Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, Texas, USA.

Beclin 1 (Becn1) is a key molecule in the autophagy pathway and has been implicated in cancer development. Due to the embryonic lethality of homozygous Becn1-deficient mice, the precise mechanisms and cell type-specific roles of Becn1 in regulating inflammation and cancer immunity remain elusive. Here, we report that myeloid-deficient Becn1 (Becn1ΔM) mice developed neutrophilia, were hypersusceptible to LPS-induced septic shock, and had a high risk of developing spontaneous precursor B cell (pre-B cell) lymphoma with elevated expression of immunosuppressive molecules programmed death ligand 1 (PD-L1) and IL-10. Becn1 deficiency resulted in the stabilization of MEKK3 and aberrant p38 activation in neutrophils, and mediated neutrophil-B cell interaction through Cxcl9/Cxcr3 chemotaxis. Neutrophil-B cell interplay further led to the activation of IL-21/STAT3/IRF1 and CD40L/ERK signaling and PD-L1 expression; therefore, it suppressed CD8+ T cell function. Ablation of p38 in Becn1ΔM mice prevented neutrophil inflammation and B cell tumorigenesis. Importantly, the low expression of Becn1 in human neutrophils was significantly correlated with the PD-L1 levels in pre-B acute lymphoblastic lymphoma (ALL) patients. Our findings have identified myeloid Becn1 as a key regulator of cancer immunity and therapeutic target for pre-B cell lymphomas.
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http://dx.doi.org/10.1172/JCI127721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6877338PMC
December 2019

JMJD3 regulates CD4 T cell trafficking by targeting actin cytoskeleton regulatory gene Pdlim4.

J Clin Invest 2019 08 8;129(11):4745-4757. Epub 2019 Aug 8.

Institute of Bioscience and Technology, Texas A&M University Health Science Center, Houston, Texas, USA.

Histone H3K27 demethylase, JMJD3 plays a critical role in gene expression and T-cell differentiation. However, the role and mechanisms of JMJD3 in T cell trafficking remain poorly understood. Here we show that JMJD3 deficiency in CD4+ T cells resulted in an accumulation of T cells in the thymus, and reduction of T cell number in the secondary lymphoid organs. We identified PDLIM4 as a significantly down-regulated target gene in JMJD3-deficient CD4+ T cells by gene profiling and ChIP-seq analyses. We further showed that PDLIM4 functioned as an adaptor protein to interact with S1P1 and filamentous actin (F-actin), thus serving as a key regulator of T cell trafficking. Mechanistically, JMJD3 bound to the promoter and gene body regions of Pdlim4 gene and regulated its expression by interacting with zinc finger transcription factor KLF2. Our findings have identified Pdlim4 as a JMJD3 target gene that affects T-cell trafficking by cooperating with S1P1, and provided insights into the molecular mechanisms by which JMJD3 regulates genes involved in T cell trafficking.
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http://dx.doi.org/10.1172/JCI128293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6819100PMC
August 2019

Investigation of parameters that determine Nano-DC vaccine transport.

Biomed Microdevices 2019 04 4;21(2):39. Epub 2019 Apr 4.

Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX, 77030, USA.

Effective migration of dendritic cells into the lymphatic system organs is the prerequisite for a functional dendritic cell vaccine. We have previously developed a porous silicon microparticle (PSM)-based therapeutic dendritic cell vaccine (Nano-DC vaccine) where PSM serves both as the vehicle for antigen peptides and an adjuvant. Here, we analyzed parameters that determined dendritic cell uptake of PSM particles and Nano-DC vaccine accumulation in lymphatic tissues in a murine model of HER2-positive breast cancer. Our study revealed a positive correlation between sphericity of the PSM particles and their cellular uptake by circulating dendritic cells. In addition, the intravenously administered vaccines accumulated more in the spleens and inguinal lymph nodes, while the intradermally inoculated vaccines got enriched in the popliteal lymph nodes. Furthermore, mice with large tumors received more vaccines in the lymph nodes than those with small to medium size tumors. Information from this study will provide guidance on design and optimization of future therapeutic cancer vaccines.
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http://dx.doi.org/10.1007/s10544-019-0397-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6686196PMC
April 2019

Impact of microbiota on central nervous system and neurological diseases: the gut-brain axis.

J Neuroinflammation 2019 Mar 1;16(1):53. Epub 2019 Mar 1.

Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX, 77030, USA.

Development of central nervous system (CNS) is regulated by both intrinsic and peripheral signals. Previous studies have suggested that environmental factors affect neurological activities under both physiological and pathological conditions. Although there is anatomical separation, emerging evidence has indicated the existence of bidirectional interaction between gut microbiota, i.e., (diverse microorganisms colonizing human intestine), and brain. The cross-talk between gut microbiota and brain may have crucial impact during basic neurogenerative processes, in neurodegenerative disorders and tumors of CNS. In this review, we discuss the biological interplay between gut-brain axis, and further explore how this communication may be dysregulated in neurological diseases. Further, we highlight new insights in modification of gut microbiota composition, which may emerge as a promising therapeutic approach to treat CNS disorders.
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http://dx.doi.org/10.1186/s12974-019-1434-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6397457PMC
March 2019

Cancer Stem Cells and Immunosuppressive Microenvironment in Glioma.

Front Immunol 2018 21;9:2924. Epub 2018 Dec 21.

Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX, United States.

Glioma is one of the most common malignant tumors of the central nervous system and is characterized by extensive infiltrative growth, neovascularization, and resistance to various combined therapies. In addition to heterogenous populations of tumor cells, the glioma stem cells (GSCs) and other nontumor cells present in the glioma microenvironment serve as critical regulators of tumor progression and recurrence. In this review, we discuss the role of several resident or peripheral factors with distinct tumor-promoting features and their dynamic interactions in the development of glioma. Localized antitumor factors could be silenced or even converted to suppressive phenotypes, due to stemness-related cell reprogramming and immunosuppressive mediators in glioma-derived microenvironment. Furthermore, we summarize the latest knowledge on GSCs and key microenvironment components, and discuss the emerging immunotherapeutic strategies to cure this disease.
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http://dx.doi.org/10.3389/fimmu.2018.02924DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6308128PMC
October 2019

Inflammasome activation negatively regulates MyD88-IRF7 type I IFN signaling and anti-malaria immunity.

Nat Commun 2018 11 23;9(1):4964. Epub 2018 Nov 23.

Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX, 77030, USA.

The inflammasome plays a critical role in inflammation and immune responses against pathogens. However, whether or how inflammasome activation regulates type I interferon (IFN-I) signaling in the context of malaria infection remain unknown. Here we show mice deficient in inflammasome sensors AIM2, NLRP3 or adaptor Caspase-1 produce high levels of IFN-I cytokines and are resistant to lethal Plasmodium yoelii YM infection. Inactivation of inflammasome signaling reduces interleukin (IL)-1β production, but increases IFN-I production. Mechanistically, we show inflammsome activation enhances IL-1β-mediated MyD88-TRAF3-IRF3 signaling and SOCS1 upregulation. However, SOCS1 inhibits MyD88-IRF7-mediated-IFN-I signaling and cytokine production in plasmacytoid dendritic cells. By contrast, ablation of inflammsome components reduces SOCS1 induction, and relieves its inhibition on MyD88-IRF7-dependent-IFN-I signaling, leading to high levels of IFN-α/β production and host survival. Our study identifies a previously unrecognized role of inflammasome activation in the negative regulation of IFN-I signaling pathways and provides potential targets for developing effective malaria vaccines.
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http://dx.doi.org/10.1038/s41467-018-07384-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6251914PMC
November 2018

DHX29 functions as an RNA co-sensor for MDA5-mediated EMCV-specific antiviral immunity.

PLoS Pathog 2018 02 20;14(2):e1006886. Epub 2018 Feb 20.

Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX, United States of America.

Melanoma differentiation-associated gene-5 (MDA5) recognizes distinct subsets of viruses including Encephalomyocarditis virus (EMCV) of picornavirus family, but the molecular mechanisms underlying the specificity of the viral recognition of MDA5 in immune cells remain obscure. DHX29 is an RNA helicase required for the translation of 5' structured mRNA of host and many picornaviruses (such as EMCV). We identify that DXH29 as a key RNA co-sensor, plays a significant role for specific recognition and triggering anti-EMCV immunity. We have observed that DHX29 regulates MDA5-, but not RIG-I-, mediated type I interferon signaling by preferentially interacting with structured RNAs and specifically with MDA5 for enhancing MDA5-dsRNA binding affinity. Overall, our results identify a critical role for DHX29 in innate immune response and provide molecular insights into the mechanisms by which DHX29 recognizes 5' structured EMCV RNA and interacts with MDA5 for potent type I interferon signaling and antiviral immunity.
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http://dx.doi.org/10.1371/journal.ppat.1006886DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5834211PMC
February 2018

PHF20 collaborates with PARP1 to promote stemness and aggressiveness of neuroblastoma cells through activation of SOX2 and OCT4.

J Mol Cell Biol 2018 04;10(2):147-160

Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX 77030, USA.

The differentiation status of neuroblastoma (NB) strongly correlates with its clinical outcomes; however, the molecular mechanisms driving maintenance of stemness and differentiation remain poorly understood. Here, we show that plant homeodomain finger-containing protein 20 (PHF20) functions as a critical epigenetic regulator in sustaining stem cell-like phenotype of NB by using CRISPR/Cas9-based targeted knockout (KO) for high-throughput screening of gene function in NB cell differentiation. The expression of PHF20 in NB was significantly associated with high aggressiveness of the tumor and poor outcomes for NB patients. Deletion of PHF20 inhibited NB cell proliferation, invasive migration, and stem cell-like traits. Mechanistically, PHF20 interacts with poly(ADP-ribose) polymerase 1 (PARP1) and directly binds to promoter regions of octamer-binding transcription factor 4 (OCT4) and sex determining region Y-box 2 (SOX2) to modulate a histone mark associated with active transcription, trimethylation of lysine 4 on histone H3 protein subunit (H3K4me3). Overexpression of OCT4 and SOX2 restored growth and progression of PHF20 KO tumor cells. Consistently, OCT4 and SOX2 protein levels in clinical NB specimens were positively correlated with PHF20 expression. Our results establish PHF20 as a key driver of NB stem cell-like properties and aggressive behaviors, with implications for prognosis and therapy.
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http://dx.doi.org/10.1093/jmcb/mjy007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5951121PMC
April 2018

BMI1 regulates androgen receptor in prostate cancer independently of the polycomb repressive complex 1.

Nat Commun 2018 02 5;9(1):500. Epub 2018 Feb 5.

Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX, 77030, USA.

BMI1, a polycomb group (PcG) protein, plays a critical role in epigenetic regulation of cell differentiation and proliferation, and cancer stem cell self-renewal. BMI1 is upregulated in multiple types of cancer, including prostate cancer. As a key component of polycomb repressive complex 1 (PRC1), BMI1 exerts its oncogenic functions by enhancing the enzymatic activities of RING1B to ubiquitinate histone H2A at lysine 119 and repress gene transcription. Here, we report a PRC1-independent role of BMI1 that is critical for castration-resistant prostate cancer (CRPC) progression. BMI1 binds the androgen receptor (AR) and prevents MDM2-mediated AR protein degradation, resulting in sustained AR signaling in prostate cancer cells. More importantly, we demonstrate that targeting BMI1 effectively inhibits tumor growth of xenografts that have developed resistance to surgical castration and enzalutamide treatment. These results suggest that blocking BMI1 alone or in combination with anti-AR therapy can be more efficient to suppress prostate tumor growth.
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http://dx.doi.org/10.1038/s41467-018-02863-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5799368PMC
February 2018

Co-delivery of tumor antigen and dual toll-like receptor ligands into dendritic cell by silicon microparticle enables efficient immunotherapy against melanoma.

J Control Release 2018 02 8;272:72-82. Epub 2018 Jan 8.

Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX 77030, USA. Electronic address:

Despite the importance and promise of cancer vaccines for broader prevention and treatment of cancer, limited clinical responses are observed, suggesting that key rational designs are required for inducing potent immune responses against cancer. Here we report a mesoporous silicon vector (MSV) as a multi-functional microparticle for formulating an efficient cancer vaccine composed of B16 melanoma derived-tyrosinase related protein 2 (TRP2) peptide and dual toll-like receptor (TLR) agonists. We demonstrated that MSV microparticles protected the peptide from rapid degradation for prolonged antigen presentation to immune cells. Moreover, MSV enabled co-delivery of two different TLR agonists [CpG oligonucleotide and monophosphoryl lipid A (MPLA)] along with TRP2 peptide into the same dendritic cell (DC), thus increasing the efficiency and capacity of DCs to induce potent TRP2-specifc CD8 T cell responses against B16 melanoma. Furthermore, this MSV-based DC vaccine could significantly prolong the median survival of tumor-bearing mice by orchestrating effective host immune responses involving CD8 T cells, CD4 T cells and macrophages. Our study provides rational and potentially translational approach to develop durable and potent immunotherapy for patients with cancer by delivering various combinations of tumor antigens, neoantigens and innate immune agonists.
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http://dx.doi.org/10.1016/j.jconrel.2018.01.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5825289PMC
February 2018

LRRC25 inhibits type I IFN signaling by targeting ISG15-associated RIG-I for autophagic degradation.

EMBO J 2018 02 29;37(3):351-366. Epub 2017 Dec 29.

Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX, USA

The RIG-I-like receptors (RLRs) are critical for protection against RNA virus infection, and their activities must be stringently controlled to maintain immune homeostasis. Here, we report that leucine-rich repeat containing protein 25 (LRRC25) is a key negative regulator of RLR-mediated type I interferon (IFN) signaling. Upon RNA virus infection, LRRC25 specifically binds to ISG15-associated RIG-I to promote interaction between RIG-I and the autophagic cargo receptor p62 and to mediate RIG-I degradation via selective autophagy. Depletion of either LRRC25 or ISG15 abrogates RIG-I-p62 interaction as well as the autophagic degradation of RIG-I. Collectively, our findings identify a previously unrecognized role of LRRC25 in type I IFN signaling activation by which LRRC25 acts as a secondary receptor to assist RIG-I delivery to autophagosomes for degradation in a p62-dependent manner.
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http://dx.doi.org/10.15252/embj.201796781DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5793803PMC
February 2018

Tgfbr2 inactivation facilitates cellular plasticity and development of Pten-null prostate cancer.

J Mol Cell Biol 2018 08;10(4):316-330

Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX, USA.

Mutations in tumors can create a state of increased cellular plasticity that promotes resistance to treatment. Thus, there is an urgent need to develop novel strategies for identifying key factors that regulate cellular plasticity in order to combat resistance to chemotherapy and radiation treatment. Here we report that prostate epithelial cell reprogramming could be exploited to identify key factors required for promoting prostate cancer tumorigenesis and cellular plasticity. Deletion of phosphatase and tensin homolog (Pten) and transforming growth factor-beta receptor type 2 (Tgfbr2) may increase prostate epithelial cell reprogramming efficiency in vitro and cause rapid tumor development and early mortality in vivo. Tgfbr2 ablation abolished TGF-β signaling but increased the bone morphogenetic protein (BMP) signaling pathway through the negative regulator Tmeff1. Furthermore, increased BMP signaling promotes expression of the tumor marker genes ID1, Oct4, Nanog, and Sox2; ID1/STAT3/NANOG expression was inversely correlated with patient survival. Thus, our findings provide information about the molecular mechanisms by which BMP signaling pathways render stemness capacity to prostate tumor cells.
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http://dx.doi.org/10.1093/jmcb/mjx052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6161409PMC
August 2018

NLRP11 attenuates Toll-like receptor signalling by targeting TRAF6 for degradation via the ubiquitin ligase RNF19A.

Nat Commun 2017 12 7;8(1):1977. Epub 2017 Dec 7.

Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX, 77030, USA.

The adaptor protein TRAF6 has a central function in Toll-like receptor (TLR) signalling, yet the molecular mechanisms controlling its activity and stability are unclear. Here we show that NLRP11, a primate specific gene, inhibits TLR signalling by targeting TRAF6 for degradation. NLRP11 recruits the ubiquitin ligase RNF19A to catalyze K48-linked ubiquitination of TRAF6 at multiple sites, thereby leading to the degradation of TRAF6. Furthermore, deficiency in either NLRP11 or RNF19A abrogates K48-linked ubiquitination and degradation of TRAF6, which promotes activation of NF-κB and MAPK signalling and increases the production of proinflammatory cytokines. Therefore, our findings identify NLRP11 as a conserved negative regulator of TLR signalling in primate cells and reveal a mechanism by which the NLRP11-RNF19A axis targets TRAF6 for degradation.
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http://dx.doi.org/10.1038/s41467-017-02073-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5719394PMC
December 2017

Selection of reference genes for gene expression studies in human bladder cancer using SYBR-Green quantitative polymerase chain reaction.

Oncol Lett 2017 Nov 19;14(5):6001-6011. Epub 2017 Sep 19.

Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX 77030, USA.

Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) is a rapid, reliable and widely used method of studying gene expression profiles that requires appropriate normalization for accurate and reliable results. Reference genes are usually used to normalize mRNA levels; however, the expression levels of these reference genes may vary between cell types, developmental stages, species and experimental conditions. Therefore, a normalization strategy is an important precondition for reliable conclusions, with endogenous controls requiring determination for every experimental system. In the present study, 18 reference genes used in various prior studies were analyzed to determine their applicability in bladder cancer. A total of 35 matched malignant and non-malignant bladder cancer (specifically transitional cell carcinoma) tissue specimens were examined. RNA and cDNA quality was stringently controlled. Candidate reference genes were assessed using SYBR-Green RT-qPCR. mRNA abundance was compared and reference genes with distinct ranges of expression to possible target genes were excluded. Genes that were differentially expressed in matched non-cancerous and cancerous samples were also excluded, using quantification cycle analysis. Subsequently, the stability of the selected reference genes was analyzed using three different methods: geNorm, NormFinder and BestKeeper. The rarely used ribosomal protein S23 (RPS23) was the most stable single reference gene, with RPS23, tumor protein, translationally controlled 1 and RPS13 comprising the optimal reference gene set for all the bladder samples. These stable reference genes should be employed in normalization and quantification of transcript levels in future expression studies of bladder cancer-associated genes.
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http://dx.doi.org/10.3892/ol.2017.7002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5661485PMC
November 2017

Assembly of the WHIP-TRIM14-PPP6C Mitochondrial Complex Promotes RIG-I-Mediated Antiviral Signaling.

Mol Cell 2017 Oct;68(2):293-307.e5

Institute of Biosciences and Technology, College of Medicine, Texas A&M University, Houston, TX 77030, USA; Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX 77030, USA; Department of Microbiology and Immunology, Weill Cornell Medical College, Cornell University, New York, NY 10065, USA. Electronic address:

Mitochondrial antiviral signaling platform protein (MAVS) acts as a central hub for RIG-I receptor proximal signal propagation. However, key components in the assembly of the MAVS mitochondrial platform that promote RIG-I mitochondrial localization and optimal activation are still largely undefined. Employing pooled RNAi and yeast two-hybrid screenings, we report that the mitochondrial adaptor protein tripartite motif (TRIM)14 provides a docking platform for the assembly of the mitochondrial signaling complex required for maximal activation of RIG-I-mediated signaling, consisting of WHIP and protein phosphatase PPP6C. Following viral infection, the ubiquitin-binding domain in WHIP bridges RIG-I with MAVS by binding to polyUb chains of RIG-I at lysine 164. The ATPase domain in WHIP contributes to stabilization of the RIG-I-dsRNA interaction. Moreover, phosphatase PPP6C is responsible for RIG-I dephosphorylation. Together, our findings define the WHIP-TRIM14-PPP6C mitochondrial signalosome required for RIG-I-mediated innate antiviral immunity.
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http://dx.doi.org/10.1016/j.molcel.2017.09.035DOI Listing
October 2017

LRRC25 Functions as an Inhibitor of NF-κB Signaling Pathway by Promoting p65/RelA for Autophagic Degradation.

Sci Rep 2017 10 18;7(1):13448. Epub 2017 Oct 18.

Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, Texas, 77030, USA.

Nuclear factor κB (NF-κB) is a family of critical transcription factors that play a critical role in innate immune responses and inflammation, yet the molecular mechanisms responsible for its tight regulation is not fully understood. In this study, we identified LRRC25, a member of leucine-rich repeat (LRR)-containing protein family, as a negative regulator in the NF-κB signaling pathway. Ectopic expression of LRRC25 impaired NF-κB activation, whereas knockout of LRRC25 potentiated NF-κB activation and enhanced the production of inflammatory cytokines. Further study demonstrated that the LRR domain of LRRC25 interacted with the Rel Homology domain (RHD) of p65/RelA and promotes the degradation of p65/RelA. Furthermore, LRRC25 enhanced the interaction between p65/RelA and cargo receptor p62, thus facilitating the degradation of p65/RelA through autophagy pathway. Our study has not only identified LRRC25 as a novel inhibitor of NF-κB signaling pathway, but also uncovers a new mechanism of crosstalk between NF-κB signaling and autophagy pathways.
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http://dx.doi.org/10.1038/s41598-017-12573-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5647368PMC
October 2017

USP26 functions as a negative regulator of cellular reprogramming by stabilising PRC1 complex components.

Nat Commun 2017 08 24;8(1):349. Epub 2017 Aug 24.

Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX, 77030, USA.

Despite much progress in the comprehension of the complex process of somatic cell reprogramming, many questions regarding the molecular mechanism of regulation remain to be answered. At present, the knowledge on the negative regulation of reprogramming process is indeed poor in contrary to the identification of positive regulators. Here we report for the first time that ubiquitin-specific protease 26 negatively regulates somatic cell-reprogramming process by stabilizing chromobox (CBX)-containing proteins CBX4 and CBX6 of polycomb-repressive complex 1 through the removal of K48-linked polyubiquitination. Thus, accumulated CBX4 and CBX6 repress the expression of pluripotency genes, such as Sox2 and Nanog, through PRC1 complexes to ubiquitinate histone H2A at their promoters. In all, our findings have revealed an essential role for ubiquitin-specific protease 26 in cellular reprogramming through polycomb-repressive complex 1.The ubiquitin-proteasome system regulates cellular reprogramming by degradation of key pluripotency factors. Here the authors report that the post-translational regulation of PRC1 components CBX4 and CBX6 by ubiquitination influences reprogramming.
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http://dx.doi.org/10.1038/s41467-017-00301-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5571198PMC
August 2017

TRIM45 functions as a tumor suppressor in the brain via its E3 ligase activity by stabilizing p53 through K63-linked ubiquitination.

Cell Death Dis 2017 05 25;8(5):e2831. Epub 2017 May 25.

Center for Inflammation and Epigenetics, Houston Methodist Research Institute, 6670 Betner Avenue, Houston, TX 77096, USA.

Tripartite motif-containing protein 45 (TRIM45) belongs to a large family of RING-finger-containing E3 ligases, which are highly expressed in the brain. However, little is known regarding the role of TRIM45 in cancer biology, especially in human glioma. Here, we report that TRIM45 expression is significantly reduced in glioma tissue samples. Overexpression of TRIM45 suppresses proliferation and tumorigenicity in glioblastoma cells in vitro and in vivo. In addition, CRISPR/Cas9-mediated knockout of TRIM45 promotes proliferation and inhibits apoptosis in glioblastoma cells. Further mechanistic analyses show that TRIM45 interacts with and stabilizes p53. TRIM45 conjugates K63-linked polyubiquitin chain to the C-terminal six lysine residues of p53, thereby inhibiting the availability of these residues to the K48-linked polyubiquitination that targets p53 for degradation. These findings suggest that TRIM45 is a novel tumor suppressor that stabilizes and activates p53 in glioma.
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http://dx.doi.org/10.1038/cddis.2017.149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5520693PMC
May 2017

Noninvasive imaging of c(RGD) -9R as a potential delivery carrier for transfection of siRNA in malignant tumors.

J Labelled Comp Radiopharm 2017 07 30;60(9):385-393. Epub 2017 May 30.

Department of Nuclear Medicine, Peking University First Hospital, Beijing, China.

The purpose of our study was to develop and evaluate a novel integrin α β -specific delivery carrier for transfection of siRNA in malignant tumors. We adopted arginine-glycine-aspartate (RGD) motif as a tissue target for specific recognition of integrin α β . A chimaeric peptide was synthesized by adding nonamer arginine residues (9-arginine [9R]) at the carboxy terminus of cyclic-RGD dimer, designated as c(RGD) -9R, to enable small interfering RNA (siRNA) binding. To test the applicability of the delivery carrier in vivo, c(RGD) -9R was labeled with radionuclide of technetium-99m. Biodistribution and γ-camera imaging studies were performed in HepG2 xenograft-bearing nude mice. As results, an optimal 10:1 molar ratio of Tc-c(RGD) -9R to siRNA was indicated by the electrophoresis on agarose gels. Tc-c(RGD) -9R/siRNA remained stable under a set of conditions in vitro. For in vivo study, tumor radioactivity uptake of Tc-c(RGD) -9R/siRNA in nude mice bearing HepG2 xenografts was significantly higher than that of control probe (P < .05). The xenografts were clearly visualized at 4 hours till 6 hours noninvasively after intravenous injection of Tc-c(RGD) -9R/siRNA, while the xenografts were not visualized at any time after injection of control probe. It was concluded that c(RGD) -9R could be an effective siRNA delivery carrier. Technetium-99m radiolabeled-delivery carrier represents a potential imaging strategy for RNAi-based therapy.
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http://dx.doi.org/10.1002/jlcr.3514DOI Listing
July 2017

A special issue on cancer immunotherapy.

Authors:
Rong-Fu Wang

Cell Res 2017 01;27(1):1-2

Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX 77030, USA.

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http://dx.doi.org/10.1038/cr.2017.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5223239PMC
January 2017

FOSL1 Inhibits Type I Interferon Responses to Malaria and Viral Infections by Blocking TBK1 and TRAF3/TRIF Interactions.

mBio 2017 01 3;8(1). Epub 2017 Jan 3.

Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, Texas, USA

Innate immune response plays a critical role in controlling invading pathogens, but such an immune response must be tightly regulated. Insufficient or overactivated immune responses may lead to harmful or even fatal consequences. To dissect the complex host-parasite interactions and the molecular mechanisms underlying innate immune responses to infections, here we investigate the role of FOS-like antigen 1 (FOSL1) in regulating the host type I interferon (IFN-I) response to malaria parasite and viral infections. FOSL1 is known as a component of a transcription factor but was recently implicated in regulating the IFN-I response to malaria parasite infection. Here we show that FOSL1 can act as a negative regulator of IFN-I signaling. Upon stimulation with poly(I:C), malaria parasite-infected red blood cells (iRBCs), or vesicular stomatitis virus (VSV), FOSL1 "translocated" from the nucleus to the cytoplasm, where it inhibited the interactions between TNF receptor-associated factor 3 (TRAF3), TIR domain-containing adapter inducing IFN-β (TRIF), and Tank-binding kinase 1 (TBK1) via impairing K63-linked polyubiquitination of TRAF3 and TRIF. Importantly, FOSL1 knockout chimeric mice had lower levels of malaria parasitemia or VSV titers in peripheral blood and decreased mortality compared with wild-type (WT) mice. Thus, our findings have identified a new role for FOSL1 in negatively regulating the host IFN-I response to malaria and viral infections and have identified a potential drug target for controlling malaria and other diseases.

Importance: Infections of pathogens can trigger vigorous host immune responses, including activation and production of type I interferon (IFN-I). In this study, we investigated the role of FOSL1, a molecule previously known as a transcription factor, in negatively regulating IFN-I responses to malaria and viral infections. We showed that FOSL1 was upregulated and translocated into the cytoplasm of cells after stimulation for IFN-I production. FOSL1 could affect TRAF3 and TRIF ubiquitination and consequently impaired the association of TRAF3, TRIF, and TBK1, leading to inhibition of IFN-I signaling. In vivo experiments with FOSL1 knockout chimeric mice further validated the negative role of FOSL1 in IFN-I production and antimicrobial responses. This report reveals a new functional role for FOSL1 in IFN-I signaling and dissects the mechanism by which FOSL1 regulates IFN-I responses to malaria and viral infections, which can be explored as a potential drug target for disease control and management.
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http://dx.doi.org/10.1128/mBio.02161-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5210502PMC
January 2017
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