TY - JOUR
T1 - Cullin-3–RING ubiquitin ligase activity is required for striated muscle function in mice
AU - Papizan, James B.
AU - Vidal, Alexander H.
AU - Bezprozvannaya, Svetlana
AU - Bassel-Duby, Rhonda
AU - Olson, Eric N.
N1 - Funding Information:
This work was supported in part by National Institutes of Health Grants AR-067294, HL-130253, and DK-099653 and Robert A. Welch Foundation Grant 1-0025 (to E. N. O.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. 1 Supported by Ruth L. Kirschstein NRSA F32 National Institutes of Health Training Grant 5F32HL123323-03. We thank Jose Cabrera for help with graphics. We also thank James Richardson and Bret Evers for assistance with histology. We are grateful to M. Arthur Moseley, Erik Soderblom, and the Duke University School of Medicine for the use of the Proteomics and Metabolomics Shared Resource. We thank R. Reid Townsend and Jim Malone for use of the Proteomics Core Laboratories at Washington University School of Medicine.
Funding Information:
This work was supported in part by National Institutes of Health Grants AR-067294, HL-130253, and DK-099653 and Robert A. Welch Foundation Grant 1-0025 (to E. N. O.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the respon-sibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Publisher Copyright:
© 2018 Papizan et al.
PY - 2018/6/8
Y1 - 2018/6/8
N2 - Control of protein homeostasis is an essential cellular process that, when perturbed, can result in the deregulation or toxic accumulation of proteins. Owing to constant mechanical stress, striated muscle proteins are particularly prone to wear and tear and require several protein quality– control mechanisms to coordinate protein turnover and removal of damaged proteins. Kelch-like proteins, substrate adapters for the Cullin-3 (Cul3)-RING ligase (CRL3) complex, are emerging as critical regulators of striated muscle development and function, highlighting the importance of Cul3-mediated proteostasis in muscle function. To explore the role of Cul3-mediated proteostasis in striated muscle, here we deleted Cul3 specifically in either skeletal muscle (SkM-Cul3 KO) or cardiomyocytes (CM-Cul3 KO) of mice. The loss of Cul3 caused neonatal lethality and dramatic alterations in the proteome, which were unique to each striated muscle type. Many of the proteins whose expression was significantly changed in the SkM-Cul3 KO were components of the extracellular matrix and sarcomere, whereas proteins altered in the CM-Cul3 KO were involved in metabolism. These findings highlight the requirement for striated muscle–specific CRL3 activity and indicate how the CRL3 complex can control different nodes of protein interaction networks in different types of striated muscle. Further identification of Cul3 substrates, and how these substrates are targeted, may reveal therapeutic targets and treatment regimens for striated muscle diseases.
AB - Control of protein homeostasis is an essential cellular process that, when perturbed, can result in the deregulation or toxic accumulation of proteins. Owing to constant mechanical stress, striated muscle proteins are particularly prone to wear and tear and require several protein quality– control mechanisms to coordinate protein turnover and removal of damaged proteins. Kelch-like proteins, substrate adapters for the Cullin-3 (Cul3)-RING ligase (CRL3) complex, are emerging as critical regulators of striated muscle development and function, highlighting the importance of Cul3-mediated proteostasis in muscle function. To explore the role of Cul3-mediated proteostasis in striated muscle, here we deleted Cul3 specifically in either skeletal muscle (SkM-Cul3 KO) or cardiomyocytes (CM-Cul3 KO) of mice. The loss of Cul3 caused neonatal lethality and dramatic alterations in the proteome, which were unique to each striated muscle type. Many of the proteins whose expression was significantly changed in the SkM-Cul3 KO were components of the extracellular matrix and sarcomere, whereas proteins altered in the CM-Cul3 KO were involved in metabolism. These findings highlight the requirement for striated muscle–specific CRL3 activity and indicate how the CRL3 complex can control different nodes of protein interaction networks in different types of striated muscle. Further identification of Cul3 substrates, and how these substrates are targeted, may reveal therapeutic targets and treatment regimens for striated muscle diseases.
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U2 - 10.1074/jbc.RA118.002104
DO - 10.1074/jbc.RA118.002104
M3 - Article
C2 - 29653945
AN - SCOPUS:85048248406
VL - 293
SP - 8802
EP - 8811
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 23
ER -