Eibach Yvonne, Kreher Silke, Poetsch Mareike S, Kho Ay Lin, Gaertner Ulrich, Clemen Christoph S, Schröder Rolf, Guo Kai, Milting Hendrik, Meder Benjamin, Potente Michael, Richter Manfred, Schneider Andre, Meiners Silke, Gautel Mathias, Braun Thomas
Department of Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
German Center for Cardiovascular Research (DZHK), Berlin, Germany.
Sci Adv. 2025 Jan 24;11(4):eado3852. doi: 10.1126/sciadv.ado3852. Epub 2025 Jan 22.
Protein homeostasis is crucial for maintaining cardiomyocyte (CM) function. Disruption of proteostasis results in accumulation of protein aggregates causing cardiac pathologies such as hypertrophy, dilated cardiomyopathy (DCM), and heart failure. Here, we identify ubiquitin-specific peptidase 5 (USP5) as a critical determinant of protein quality control (PQC) in CM. CM-specific loss of leads to the accumulation of polyubiquitin chains and protein aggregates, cardiac remodeling, and eventually DCM. USP5 interacts with key components of the proteostasis machinery, including PSMD14, and the absence of USP5 increases activity of the ubiquitin-proteasome system and autophagic flux in CMs. Cardiac-specific overexpression reduces pathological remodeling in pressure-overloaded mouse hearts and attenuates protein aggregate formation in titinopathy and desminopathy models. Since CMs from humans with end-stage DCM show lower USP5 levels and display accumulation of ubiquitinated protein aggregates, we hypothesize that therapeutically increased USP5 activity may reduce protein aggregates during DCM. Our findings demonstrate that USP5 is essential for ubiquitin turnover and proteostasis in mature CMs.
蛋白质稳态对于维持心肌细胞（CM）功能至关重要。蛋白稳态的破坏会导致蛋白质聚集体的积累，从而引发诸如肥大、扩张型心肌病（DCM）和心力衰竭等心脏疾病。在此，我们确定泛素特异性肽酶5（USP5）是心肌细胞中蛋白质质量控制（PQC）的关键决定因素。心肌细胞特异性缺失会导致多聚泛素链和蛋白质聚集体的积累、心脏重塑，并最终导致扩张型心肌病。USP5与蛋白稳态机制的关键成分相互作用，包括蛋白酶体亚基14（PSMD14），而USP5的缺失会增加心肌细胞中泛素-蛋白酶体系统的活性和自噬通量。心脏特异性过表达可减少压力超负荷小鼠心脏的病理重塑，并减轻肌联蛋白病和结蛋白病模型中蛋白质聚集体的形成。由于终末期扩张型心肌病患者的心肌细胞显示出较低的USP5水平，并出现泛素化蛋白质聚集体的积累，我们推测通过治疗提高USP5活性可能会减少扩张型心肌病期间的蛋白质聚集体。我们的研究结果表明，USP5对于成熟心肌细胞中的泛素周转和蛋白稳态至关重要。
