Journal
JOURNAL OF CELL SCIENCE
Volume 132, Issue 17, Pages -Publisher
COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.233395
Keywords
Atrophy; Cullin; MuRF1
Categories
Funding
- Deutsche Forschungsgemeinschaft [FI 965/4-1, SO 271/6-1]
- MaxDelbruck-Center for Molecular Medicine
- Experimental and Clinical Research Center (ECRC)
- GO-Bio Initiative of the German Federal Ministry for Education and Research (Bundesministerium fur Bildung und Forschung) [0313881]
- ERA-NET NEURON initiative - BMBF [01W1301]
- Berlin Institute of Health Collaborative Research - BMBF [1.1.2. a. 3]
- Helmholtz Validation Fund - Helmholtz Association, Germany [HVF-0013]
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The muscle-specific RING-finger protein MuRF1 (also known as TRIM63) constitutes a bona fide ubiquitin ligase that routes proteins like several different myosin heavy chain proteins (MyHC) to proteasomal degradation during muscle atrophy. In two unbiased screens, we identified DCAF8 as a new MuRF1-binding partner. MuRF1 physically interacts with DCAF8 and both proteins localize to overlapping structures in muscle cells. Importantly, similar to what is seen for MuRF1, DCAF8 levels increase during atrophy, and the downregulation of either protein substantially impedes muscle wasting and MyHC degradation in C2C12 myotubes, a model system for muscle differentiation and atrophy. DCAF proteins typically serve as substrate receptors for cullin 4-type (Cul4) ubiquitin ligases (CRL), and we demonstrate that DCAF8 and MuRF1 associate with the subunits of such a protein complex. Because genetic downregulation of DCAF8 and inhibition of cullin activity also impair myotube atrophy in C2C12 cells, our data imply that the DCAF8 promotes muscle wasting by targeting proteins like MyHC as an integral substrate receptor of a Cul4A-containing ring ubiquitin ligase complex (CRL4A). This article has an associated First Person interview with the first author of the paper.
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