TY - JOUR
T1 - KLHL41 stabilizes skeletal muscle sarcomeres by nonproteolytic ubiquitination
AU - Ramirez-Martinez, Andres
AU - Cenik, Bercin Kutluk
AU - Bezprozvannaya, Svetlana
AU - Chen, Beibei
AU - Bassel-Duby, Rhonda
AU - Liu, Ning
AU - Olson, Eric N.
N1 - Publisher Copyright:
© Ramirez-Martinez et al.
PY - 2017/8/9
Y1 - 2017/8/9
N2 - Maintenance of muscle function requires assembly of contractile proteins into highly organized sarcomeres. Mutations in Kelch-like protein 41 (KLHL41) cause nemaline myopathy, a fatal muscle disorder associated with sarcomere disarray. We generated KLHL41 mutant mice, which display lethal disruption of sarcomeres and aberrant expression of muscle structural and contractile proteins, mimicking the hallmarks of the human disease. We show that KLHL41 is polyubiquitinated and acts, at least in part, by preventing aggregation and degradation of Nebulin, an essential component of the sarcomere. Furthermore, inhibition of KLHL41 poly-ubiquitination prevents its stabilization of nebulin, suggesting a unique role for ubiquitination in protein stabilization. These findings provide new insights into the molecular etiology of nemaline myopathy and reveal a mechanism whereby KLHL41 stabilizes sarcomeres and maintains muscle function by acting as a molecular chaperone. Similar mechanisms for protein stabilization likely contribute to the actions of other Kelch proteins.
AB - Maintenance of muscle function requires assembly of contractile proteins into highly organized sarcomeres. Mutations in Kelch-like protein 41 (KLHL41) cause nemaline myopathy, a fatal muscle disorder associated with sarcomere disarray. We generated KLHL41 mutant mice, which display lethal disruption of sarcomeres and aberrant expression of muscle structural and contractile proteins, mimicking the hallmarks of the human disease. We show that KLHL41 is polyubiquitinated and acts, at least in part, by preventing aggregation and degradation of Nebulin, an essential component of the sarcomere. Furthermore, inhibition of KLHL41 poly-ubiquitination prevents its stabilization of nebulin, suggesting a unique role for ubiquitination in protein stabilization. These findings provide new insights into the molecular etiology of nemaline myopathy and reveal a mechanism whereby KLHL41 stabilizes sarcomeres and maintains muscle function by acting as a molecular chaperone. Similar mechanisms for protein stabilization likely contribute to the actions of other Kelch proteins.
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U2 - 10.7554/eLife.26439
DO - 10.7554/eLife.26439
M3 - Article
C2 - 28826497
AN - SCOPUS:85029429515
SN - 2050-084X
VL - 6
JO - eLife
JF - eLife
M1 - e26439
ER -