MassIVE MSV000084538

Partial Public PXD016139

ATF4 Promotes Skeletal Muscle Atrophy by Forming a Heterodimer with C/EBPbeta

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Description

Skeletal muscle atrophy is a highly prevalent and debilitating condition that remains poorly understood at the molecular level. Previous work found that skeletal muscle atrophy involves activating transcription factor 4 (ATF4), a protein in the basic leucine zipper (bZIP) transcription factor family. However, the direct biochemical mechanism by which ATF4 promotes muscle atrophy was unknown. Because bZIP proteins such as ATF4 must dimerize to bind and activate genes, and because ATF4 is unable to form highly stable homodimers, we hypothesized that ATF4 may promote muscle atrophy by heterodimerizing with another bZIP family member. To test this hypothesis, we biochemically isolated skeletal muscle proteins that associate with the dimerization- and DNA-binding domain of ATF4 (the bZIP domain) in mouse skeletal muscle fibers in vivo. Interestingly, we found that ATF4 makes up one half of at least 5 distinct heterodimeric bZIP transcription factors in skeletal muscle fibers. This three-way interaction between ATF4, C/EBPbeta and the ATF4-C/EBP composite site activates the Gadd45a gene, which encodes a known mediator of muscle atrophy (Gadd45a). Together, these results identify a direct biochemical mechanism by which ATF4 induces skeletal muscle atrophy and provide new insight into the way that skeletal muscle atrophy occurs at the molecular level. [doi:10.25345/C54T1D] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: sarcopenia ; data-independent acquisition ; Skyline ; Interacting proteins ; bzip domaine

Contact

Principal Investigators:
(in alphabetical order) 		Birgit Schilling, Buck Institute for Research on Aging, United States
Submitting User: bschilling
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