title: KLHL40 deficiency destabilizes thin filament proteins and promotes nemaline myopathy.
abstract: Nemaline myopathy (NM) is a congenital myopathy that can result in lethal muscle dysfunction and is thought to be a disease of the sarcomere thin filament. Recently, several proteins of unknown function have been implicated in NM, but the mechanistic basis of their contribution to disease remains unresolved. Here, we demonstrated that loss of a muscle-specific protein, kelch-like family member 40 (KLHL40), results in a nemaline-like myopathy in mice that closely phenocopies muscle abnormalities observed in KLHL40-deficient patients. We determined that KLHL40 localizes to the sarcomere I band and A band and binds to nebulin (NEB), a protein frequently implicated in NM, as well as a putative thin filament protein, leiomodin 3 (LMOD3). KLHL40 belongs to the BTB-BACK-kelch (BBK) family of proteins, some of which have been shown to promote degradation of their substrates. In contrast, we found that KLHL40 promotes stability of NEB and LMOD3 and blocks LMOD3 ubiquitination. Accordingly, NEB and LMOD3 were reduced in skeletal muscle of both Klhl40-/- mice and KLHL40-deficient patients. Loss of sarcomere thin filament proteins is a frequent cause of NM; therefore, our data that KLHL40 stabilizes NEB and LMOD3 provide a potential basis for the development of NM in KLHL40-deficient patients.
authors: Ankit
authors: A
authors: Garg
authors: Jason
authors: J
authors: O'Rourke
authors: Chengzu
authors: C
authors: Long
authors: Jonathan
authors: J
authors: Doering
authors: Gianina
authors: G
authors: Ravenscroft
authors: Svetlana
authors: S
authors: Bezprozvannaya
authors: Benjamin R
authors: BR
authors: Nelson
authors: Nadine
authors: N
authors: Beetz
authors: Lin
authors: L
authors: Li
authors: She
authors: S
authors: Chen
authors: Nigel G
authors: NG
authors: Laing
authors: Robert W
authors: RW
authors: Grange
authors: Rhonda
authors: R
authors: Bassel-Duby
authors: Eric N
authors: EN
authors: Olson
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D017696:Myopathies, Nemaline / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D054730:Protein Interaction Domains and Motifs; D055550:Protein Stability; D059748:Proteolysis; D012518:Sarcomeres / Q000378:metabolism / Q000473:pathology; D054875:Ubiquitination
chemical_list: D003598:Cytoskeletal Proteins; C000593493:Kbtbd5 protein, mouse; D009124:Muscle Proteins; C523689:leiomodin protein, mouse; C035620:nebulin