Role of a TRIM72 ADP-ribosylation cycle in myocardial injury and membrane repair.

JCI Insight 2018 11 15;3(22). Epub 2018 Nov 15.

Pulmonary Branch.

Mono-ADP-ribosylation of an (arginine) protein catalyzed by ADP-ribosyltransferase 1 (ART1) - i.e., transfer of ADP-ribose from NAD to arginine - is reversed by ADP-ribosylarginine hydrolase 1 (ARH1) cleavage of the ADP-ribose-arginine bond. ARH1-deficient mice developed cardiomyopathy with myocardial fibrosis, decreased myocardial function under dobutamine stress, and increased susceptibility to ischemia/reperfusion injury. The membrane repair protein TRIM72 was identified as a substrate for ART1 and ARH1; ADP-ribosylated TRIM72 levels were greater in ARH1-deficient mice following ischemia/reperfusion injury. To understand better the role of TRIM72 and ADP-ribosylation, we used C2C12 myocytes. ARH1 knockdown in C2C12 myocytes increased ADP-ribosylation of TRIM72 and delayed wound healing in a scratch assay. Mutant TRIM72 (R207K, R260K) that is not ADP-ribosylated interfered with assembly of TRIM72 repair complexes at a site of laser-induced injury. The regulatory enzymes ART1 and ARH1 and their substrate TRIM72 were found in multiple complexes, which were coimmunoprecipitated from mouse heart lysates. In addition, the mono-ADP-ribosylation inhibitors vitamin K1 and novobiocin inhibited oligomerization of TRIM72, the mechanism by which TRIM72 is recruited to the site of injury. We propose that a mono-ADP-ribosylation cycle involving recruitment of TRIM72 and other regulatory factors to sites of membrane damage is critical for membrane repair and wound healing following myocardial injury.

Download full-text PDF

Source
https://insight.jci.org/articles/view/97898
Publisher Site
http://dx.doi.org/10.1172/jci.insight.97898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6302937PMC
November 2018
38 Reads

Publication Analysis

Top Keywords

membrane repair
12
trim72
10
arh1-deficient mice
8
myocardial injury
8
ischemia/reperfusion injury
8
art1 arh1
8
wound healing
8
injury membrane
8
trim72 adp-ribosylation
8
c2c12 myocytes
8
role trim72
8
injury
6
trim72 levels
4
mouse heart
4
understand better
4
adp-ribosylated trim72
4
coimmunoprecipitated mouse
4
greater arh1-deficient
4
injury understand
4
complexes coimmunoprecipitated
4

Similar Publications