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

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

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Article numbere2200215119
JournalProceedings of the National Academy of Sciences of the United States of America
Volume119
Issue number43
DOIs
StatePublished - 25 Oct 2022
Externally publishedYes

Keywords

  • MHC-IIb
  • MHC-IIx
  • UBR2
  • cancer cachexia
  • ubiquitylation

Fingerprint

Dive into the research topics of 'UBR2 targets myosin heavy chain IIb and IIx for degradation: Molecular mechanism essential for cancer-induced muscle wasting'. Together they form a unique fingerprint.

Cite this