Cullin-3–RING ubiquitin ligase activity is required for striated muscle function in mice

Abstract

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.

Cul3regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development

“…5c and Supplementary Table 4). Overall, and in agreement with previous observations 30-32 , the observed fold changes were mild, in line with the hypothesis that the ubiquitylated isoform of a protein represents only a small fraction of the total pool of that given protein at any time point 33 . We noticed, however, that proteins with abnormal levels in Cul3 homozygous mutants are significantly enriched for high confidence ASD-risk genes ( Cul3 fl/fl Emx1-Cre at 20% FDR, 65 genes, p= 0.0329).…”

Cullin-3–dependent deregulation of ACTN1 represents a pathogenic mechanism in nemaline myopathy

“…During preparation of the present manuscript, an article investigating the role of Cullin-3 in striated muscles was published (20). The authors demonstrated that Cullin-3 was required for striated muscle development, a finding that our studies fully support.…”

Novel KLHL26 variant associated with a familial case of Ebstein’s anomaly and left ventricular noncompaction

“…KLHL9 (Cirak et al, ), KBTBD13 (Sambuughin et al, ), KLHL40 (Ravenscroft et al, ), and KLHL41 (Gupta et al, ) have been implicated in distal and nemaline myopathy. CUL3 is enriched in muscle tissues, essential for myoblast differentiation, and conditional CM‐KO of CUL3 is neonatal lethal in mice (Blondelle, Shapiro, Domenighetti, & Lange, ; Papizan et al, ). CM deletion of NAE1, a regulatory subunit of neddylation, in mice CMs caused heart failure and perinatal lethality (Zou et al, ).…”