TY - JOUR
T1 - Gadd45a protein promotes skeletal muscle atrophy by forming a complex with the protein kinase MEKK4
AU - Bullard, Steven A.
AU - Seo, Seongjin
AU - Schilling, Birgit
AU - Dyle, Michael C.
AU - Dierdorff, Jason M.
AU - Ebert, Scott M.
AU - DeLau, Austin D.
AU - Gibson, Bradford W.
AU - Adams, Christopher M.
N1 - Funding Information:
This work was supported by National Institutes of Health Grants R01AR059115 and R01EY022616, United States Department of Veterans Affairs Biomedical Laboratory Research and Development Service Grant IBX000976A, the United States Department of Veterans Affairs Rehabilitation and Research Development Service Grant 1I01RX001477, the Fraternal Order of Eagles Diabetes Research Center at the University of Iowa, and National Institutes of Health Shared Instrumentation Grant 1S10 OD016281 for the TripleTOF mass spectrometric system at the Buck Institute (to B. W. G.). C. M. A., S. M. E., and M. C. D. hold equity in Emmyon, Inc. C. M. A. is a founder and officer of Emmyon, Inc. S. M. E. and M. C. D. are employees of Emmyon, Inc. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
PY - 2016/8/19
Y1 - 2016/8/19
N2 - Skeletal muscle atrophy is a serious and highly prevalent condition that remains poorly understood at the molecular level. Previous work found that skeletal muscle atrophy involves an increase in skeletal muscle Gadd45a expression, which is necessary and sufficient for skeletal muscle fiber atrophy. However, the direct mechanism by which Gadd45a promotes skeletal muscle atrophy was unknown. To address this question, we biochemically isolated skeletal muscle proteins that associate with Gadd45a as it induces atrophy in mouse skeletal muscle fibers in vivo.Wefound that Gadd45a interacts with multiple proteins in skeletal muscle fibers, including, most prominently, MEKK4, a mitogen-activated protein kinase kinase kinase that was not previously known to play a role in skeletal muscle atrophy. Furthermore, we found that, by forming a complex with MEKK4 in skeletal muscle fibers, Gadd45a increases MEKK4 protein kinase activity, which is both sufficient to induce skeletal muscle fiber atrophy and required for Gadd45a-mediated skeletal muscle fiber atrophy. Together, these results identify a direct biochemical mechanism by which Gadd45a induces skeletal muscle atrophy and provide new insight into the way that skeletal muscle atrophy occurs at the molecular level.
AB - Skeletal muscle atrophy is a serious and highly prevalent condition that remains poorly understood at the molecular level. Previous work found that skeletal muscle atrophy involves an increase in skeletal muscle Gadd45a expression, which is necessary and sufficient for skeletal muscle fiber atrophy. However, the direct mechanism by which Gadd45a promotes skeletal muscle atrophy was unknown. To address this question, we biochemically isolated skeletal muscle proteins that associate with Gadd45a as it induces atrophy in mouse skeletal muscle fibers in vivo.Wefound that Gadd45a interacts with multiple proteins in skeletal muscle fibers, including, most prominently, MEKK4, a mitogen-activated protein kinase kinase kinase that was not previously known to play a role in skeletal muscle atrophy. Furthermore, we found that, by forming a complex with MEKK4 in skeletal muscle fibers, Gadd45a increases MEKK4 protein kinase activity, which is both sufficient to induce skeletal muscle fiber atrophy and required for Gadd45a-mediated skeletal muscle fiber atrophy. Together, these results identify a direct biochemical mechanism by which Gadd45a induces skeletal muscle atrophy and provide new insight into the way that skeletal muscle atrophy occurs at the molecular level.
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U2 - 10.1074/jbc.M116.740308
DO - 10.1074/jbc.M116.740308
M3 - Article
C2 - 27358404
AN - SCOPUS:84983467281
SN - 0021-9258
VL - 291
SP - 17496
EP - 17509
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 34
ER -