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Inadequate ubiquitination-proteasome coupling contributes to myocardial ischemia-reperfusion injury
Chengjun Hu, … , Jinbao Liu, Xuejun Wang
Chengjun Hu, … , Jinbao Liu, Xuejun Wang
Published September 11, 2018
Citation Information: J Clin Invest. 2018;128(12):5294-5306. https://doi.org/10.1172/JCI98287.
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Research Article Cardiology

Inadequate ubiquitination-proteasome coupling contributes to myocardial ischemia-reperfusion injury

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Abstract

The ubiquitin-proteasome system (UPS) degrades a protein molecule via 2 main steps: ubiquitination and proteasomal degradation. Extraproteasomal ubiquitin receptors are thought to couple the 2 steps, but this proposition has not been tested in vivo with vertebrates. More importantly, impaired UPS performance plays a major role in cardiac pathogenesis, including myocardial ischemia-reperfusion injury (IRI), but the molecular basis of UPS impairment remains poorly understood. Ubiquilin1 is a bona fide extraproteasomal ubiquitin receptor. Here, we report that mice with a cardiomyocyte-restricted knockout of Ubiquilin1 (Ubqln1-CKO mice) accumulated a surrogate UPS substrate (GFPdgn) and increased myocardial ubiquitinated proteins without altering proteasome activities, resulting in late-onset cardiomyopathy and a markedly shortened life span. When subject to regional myocardial ischemia-reperfusion, young Ubqln1-CKO mice showed substantially exacerbated cardiac malfunction and enlarged infarct size, and conversely, mice with transgenic Ubqln1 overexpression displayed attenuated IRI. Furthermore, Ubqln1 overexpression facilitated proteasomal degradation of oxidized proteins and the degradation of a UPS surrogate substrate in cultured cardiomyocytes without increasing autophagic flux. These findings demonstrate that Ubiquilin1 is essential to cardiac ubiquitination-proteasome coupling and that an inadequacy in the coupling represents a major pathogenic factor for myocardial IRI; therefore, strategies to strengthen coupling have the potential to reduce IRI.

Authors

Chengjun Hu, Yihao Tian, Hongxin Xu, Bo Pan, Erin M. Terpstra, Penglong Wu, Hongmin Wang, Faqian Li, Jinbao Liu, Xuejun Wang

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Figure 4

Ubqln1-CKO impairs myocardial UPS performance without affecting proteasome peptidase activities at 3 weeks of age.

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Ubqln1-CKO impairs myocardial UPS performance without affecting proteaso...
(A and B) Representative image (A) and pooled densitometry data (B) of Western blot analyses for the indicated proteins in ventricular myocardial samples. Tg GFPdgn was introduced into Ubqlin1-CKO and control background through mouse crossbreeding. (C–H) Myocardial proteasomal peptidase activity assays. Crude protein extracts from the ventricular myocardium of homozygous Ubqln1-CKO mice and littermate control (combining Ubqln1fl/fl and heterozygous Ubqln1-CKO) mice as well as from a Tg mouse model of desmin-related cardiomyopathy serving as a positive control [(+)CTL] for the assays were assayed for their 20S and 26S proteasomal chymotrypsin-like (C and D), caspase-like (E and F), and trypsin-like (G and H) activities using specific fluorogenic substrates. The P values between control and Ubqln1-CKO groups were derived from 2-tailed unpaired t test with Welch’s correction. *P < 0.05; **P < 0.01; ***P < 0.005 vs. control and Ubqln1-CKO, Welch’s ANOVA followed by Tukey’s test for pair-wise comparison. Each dot and each lane in Western blot represents an independent mouse.
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