TRIM23 mediates virus-induced autophagy via activation of TBK1.

Nat Microbiol 2017 Nov 4;2(11):1543-1557. Epub 2017 Sep 4.

Department of Microbiology, The University of Chicago, Chicago, IL, 60637, USA.

Autophagy and interferon (IFN)-mediated innate immunity are critical antiviral defence mechanisms, and recent evidence indicated that tripartite motif (TRIM) proteins are important regulators of both processes. Although the role of TRIM proteins in modulating antiviral cytokine responses has been well established, much less is known about their involvement in autophagy in response to different viral pathogens. Through a targeted RNAi screen examining the relevance of selected TRIM proteins in autophagy induced by herpes simplex virus 1 (HSV-1), encephalomyocarditis virus (EMCV) and influenza A virus (IAV), we identified several TRIM proteins that regulate autophagy in a virus-species-specific manner, as well as a few TRIM proteins that were essential for autophagy triggered by all three viruses and rapamycin, among them TRIM23. TRIM23 was critical for autophagy-mediated restriction of multiple viruses, and this activity was dependent on both its RING E3 ligase and ADP-ribosylation factor (ARF) GTPase activity. Mechanistic studies revealed that unconventional K27-linked auto-ubiquitination of the ARF domain is essential for the GTP hydrolysis activity of TRIM23 and activation of TANK-binding kinase 1 (TBK1) by facilitating its dimerization and ability to phosphorylate the selective autophagy receptor p62. Our work identifies the TRIM23-TBK1-p62 axis as a key component of selective autophagy and further reveals a role for K27-linked ubiquitination in GTPase-dependent TBK1 activation.

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41564-017-0017-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5658249PMC
November 2017
11 Reads

Publication Analysis

Top Keywords

trim proteins
20
autophagy
8
selective autophagy
8
trim
5
proteins
5
trim23 critical
4
critical autophagy-mediated
4
autophagy-mediated restriction
4
three viruses
4
viruses rapamycin
4
trim23 trim23
4
restriction multiple
4
rapamycin trim23
4
activity dependent
4
adp-ribosylation factor
4
factor arf
4
arf gtpase
4
ligase adp-ribosylation
4
ring ligase
4
viruses activity
4

Altmetric Statistics

References

(Supplied by CrossRef)

K Ozato et al.
Nat. Rev. Immunol. 2008

GA Versteeg et al.
Immunity 2013

B Levine et al.
Cell 2008

A Stolz et al.
Nat. Cell Biol. 2014

F Randow et al.
Cell Host Microbe 2014

MC Tal et al.
Curr. Top. Microbiol. Immunol. 2009

B Levine et al.
Nature 2011

V Deretic et al.
Nat. Rev. Immunol. 2013

S Sharma et al.
Science 2003

M Pilli et al.
Immunity 2012

B Richter et al.
Proc. Natl Acad. Sci. USA 2016

Similar Publications