Ozz-E3 ubiquitin ligase targets sarcomeric embryonic myosin heavy chain during muscle development.
Muscle contractile proteins are expressed as a series of developmental isoforms that are in constant dynamic remodeling during embryogenesis, but how obsolete molecules are recognized and removed is not known. Ozz is a developmentally regulated protein that functions as the adaptor component of a RING-type ubiquitin ligase complex specific to striated muscle. Ozz(-/-) mutants exhibit defects in myofibrillogenesis and myofiber differentiation. Here we show that Ozz targets the rod portion of embryonic myosin heavy chain and preferentially recognizes the sarcomeric rather than the soluble pool of myosin. We present evidence that Ozz binding to the embryonic myosin isoform within sarcomeric thick filaments marks it for ubiquitination and proteolytic degradation, allowing its replacement with neonatal or adult isoforms. This unique function positions Ozz within a system that facilitates sarcomeric myosin remodeling during muscle maturation and regeneration. Our findings identify Ozz-E3 as the ubiquitin ligase complex that interacts with and regulates myosin within its fully assembled cytoskeletal structure.
Campos
Yvan
Y
Department of Genetics and Tumor Cell Biology, St Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
Qiu
Xiaohui
X
Zanoteli
Edmar
E
Moshiach
Simon
S
Vergani
Naja
N
Bongiovanni
Antonella
A
Harris
A John
AJ
d'Azzo
Alessandra
A
D000818:Animals; D001284:Atrophy / Q000473:pathology; D002454:Cell Differentiation; D003599:Cytoskeleton / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D008822:Mice, Transgenic; D009132:Muscles / Q000196:embryology*; D009154:Mutation; D018995:Myosin Heavy Chains / Q000378:metabolism*; D020033:Protein Isoforms; D012097:Repressor Proteins / Q000737:chemistry / Q000502:physiology*; D012518:Sarcomeres / Q000378:metabolism*; D020798:Two-Hybrid System Techniques; D025801:Ubiquitin / Q000737:chemistry; D043743:Ubiquitin-Protein Ligase Complexes; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000502:physiology*
C482861:Neurl2 protein, mouse; D020033:Protein Isoforms; D012097:Repressor Proteins; D025801:Ubiquitin; D043743:Ubiquitin-Protein Ligase Complexes; D044767:Ubiquitin-Protein Ligases; D018995:Myosin Heavy Chains