Muscle actin is polyubiquitinylated in vitro and in vivo and targeted for breakdown by the E3 ligase MuRF1
Muscle actin is polyubiquitinylated in vitro and in vivo and targeted for breakdown by the E3 ligase MuRF1
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DOI：
10.1096/fj.11-180968
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发表时间：
2011-11-01
期刊：
影响因子：
4.8
通讯作者：
Taillandier, Daniel
中科院分区：
文献类型：
--
作者：
Polge, Cecile;Heng, Anne-Elisabeth;Taillandier, Daniel
肌肉萎缩在许多疾病中普遍存在（癌症恶病质、肾衰竭、感染等），主要是由于蛋白质水解增加，卧床休息加速了这一过程。这在很大程度上导致了医疗费用的增加。设计新的策略来预防肌肉萎缩是一个重大的临床挑战。泛素蛋白酶体系统（UPS）降解肌原纤维蛋白，但负责肌动蛋白分解的精确机制是令人惊讶的差的特点。我们报告说，嵌合旗肌动蛋白不稳定和polyubiquitinylated在稳定转染的C2 C12肌管用分解代谢剂地塞米松（1 μ M）处理，只有蛋白酶体抑制剂阻止其分解。在野生型C2 C12肌管和来自对照参与者和癌症患者的人类肌肉活检中也检测到肌动蛋白多泛素化。肌肉特异性E3泛素连接酶MuRF 1在分解代谢条件下上调，并使粗肌丝的多泛素化组分。我们还表明，重组GST-MuRF 1的物理相互作用和多泛素化的肌动蛋白在体外和MuRF 1是一个关键组成部分的肌动蛋白分解，因为MuRF 1 siRNA稳定旗肌动蛋白。这些数据明确地确定了丰富的收缩蛋白肌动蛋白作为体外和体内骨骼肌中UPS的靶标，进一步支持了对特异性阻断肌肉萎缩条件下该途径激活的新策略的需求。Polge，C. Heng，A.- E、Jarzaguet，M.，Ventadour，S.，Claustre，A.，孔巴雷湖Bechet，D.，Matondo，M.，Uttenweiler-Joseph，S.，蒙萨拉特，B.，Attaix，D.，Taillandier，D.肌肉肌动蛋白在体外和体内被聚泛素化，并被E3连接酶MuRF 1靶向分解。FASEB J.25，3790-3802（2011）。www.fasebj.org
Muscle atrophy prevails in numerous diseases (cancer cachexia, renal failure, infections, etc.), mainly results from elevated proteolysis, and is accelerated by bed rest. This largely contributes to increased health costs. Devising new strategies to prevent muscle wasting is a major clinical challenge. The ubiquitin proteasome system (UPS) degrades myofibrillar proteins, but the precise mechanisms responsible for actin breakdown are surprisingly poorly characterized. We report that chimeric flag-actin was destabilized and polyubiquitinylated in stably transfected C2C12 myotubes treated with the catabolic agent dexamethasone (1 mu M) and that only proteasome inhibitors blocked its breakdown. Actin polyubiquitinylation was also detected in wild-type C2C12 myotubes and human muscle biopsies from control participants and patients with cancer. The muscle-specific E3 ubiquitin ligase MuRF1 is up-regulated in catabolic conditions and polyubiquitinylates components of the thick filament. We also demonstrate that recombinant GST-MuRF1 physically interacted and polyubiquitinylated actin in vitro and that MuRF1 is a critical component for actin breakdown, since MuRF1 siRNA stabilized flag-actin. These data identify unambiguously the abundant contractile protein actin as a target of the UPS in skeletal muscle both in vitro and in vivo, further supporting the need for new strategies blocking specifically the activation of this pathway in muscle wasting conditions.-Polge, C., Heng, A.-E., Jarzaguet, M., Ventadour, S., Claustre, A., Combaret, L., Bechet, D., Matondo, M., Uttenweiler-Joseph, S., Monsarrat, B., Attaix, D., Taillandier, D. Muscle actin is polyubiquitinylated in vitro and in vivo and targeted for breakdown by the E3 ligase MuRF1. FASEB J. 25, 3790-3802 (2011). www.fasebj.org