UBR2 targets myosin heavy chain IIb and IIx for degradation: Molecular mechanism essential for cancer-induced muscle wasting

• DOI: 10.1073/pnas.2200215119
• Publication Date: 2022-10-17T19:10:57Z
• Authors: Song Gao; Guohua Zhang; Zicheng Zhang; James Z. Zhu; Li Li; Yong Zhou; George G. Rodney; Reem S. Abo-Zahrah; Lindsey Anderson; Jose M. Garcia; Yong Tae Kwon; Yi-Ping Li
• Keywords: 0301 basic medicine; Medical Sciences; Cachexia; Bioinformatics; Ubiquitin-Protein Ligases; Muscle Fibers, Skeletal; 610; Tropomyosin; Muscle Fibers; UBR2; Biomedical Informatics; Mice; 03 medical and health sciences; Neoplasms; Medical Specialties; Medicine and Health Sciences; Animals; ubiquitylation; Muscle, Skeletal; MHC-IIx; MHC-IIb; Nonmuscle Myosin Type IIB; Myosin Heavy Chains; Skeletal; Biological Sciences; Actins; Troponin; 3. Good health; Oncology; Muscle; cancer cachexia; Tropomodulin

Cancer cachexia is a lethal metabolic syndrome featuring muscle wasting with preferential loss of fast-twitching muscle mass through an undefined mechanism. Here, we show that cancer induces muscle wasting by selectively degrading myosin heavy chain (MHC) subtypes IIb and IIx through E3 ligase UBR2-mediated ubiquitylation. Induction of MHC loss and atrophy in C2C12 myotubes and mouse tibialis anterior (TA) by murine cancer cells required UBR2 up-regulation by cancer. Genetic gain or loss of UBR2 function inversely altered MHC level and muscle mass in TA of tumor-free mice. UBR2 selectively interacted with and ubiquitylated MHC-IIb and MHC-IIx through its substrate recognition and catalytic domain, respectively, in C2C12 myotubes. Elevation of UBR2 in muscle of tumor-bearing or free mice caused loss of MHC-IIb and MHC-IIx but not MHC-I and MHC-IIa or other myofibrillar proteins, including α-actin, troponin, tropomyosin, and tropomodulin. Muscle-specific knockout of UBR2 spared KPC tumor-bearing mice from losing MHC-IIb and MHC-IIx, fast-twitching muscle mass, cross-sectional area, and contractile force. The rectus abdominis (RA) muscle of patients with cachexia-prone cancers displayed a selective reduction of MHC-IIx in correlation with higher UBR2 levels. These data suggest that UBR2 is a regulator of MHC-IIb/IIx essential for cancer-induced muscle wasting, and that therapeutic interventions can be designed by blocking UBR2 up-regulation by cancer.