title: PDLIM7 is a novel target of the ubiquitin ligase Nedd4-1 in skeletal muscle.
abstract: Skeletal muscle atrophy remains a complication occurring both as a natural response to muscle disuse and as a pathophysiological response to illness such as diabetes mellitus and nerve injury, such as traumatic muscle denervation. The ubiquitin-proteasome system (UPS) is the predominant proteolytic machinery responsible for atrophy of skeletal muscle, and Nedd4-1 (neural precursor cell-expressed developmentally down-regulated 4-1) is one of a series of E3 ubiquitin ligases identified to mediate inactivity-induced muscle wasting. Targets of Nedd4-1 mediated ubiquitination in skeletal muscle remain poorly understood. In the present study, we identified PDLIM7 (PDZ and LIM domain 7, Enigma), a member of the PDZ-LIM family of proteins, as a novel target of Nedd4-1 in skeletal muscle. The PDZ-LIM family of proteins is known to regulate muscle development and function. We show that Nedd4-1 expression in muscle atrophied by denervation is co-incident with a decrease in PDLIM7 and that PDLIM7 protein levels are stabilized in denervated muscle of Nedd4-1 skeletal muscle-specific knockout mice (SMS-KO). Exogenous PDLIM7 and Nedd4-1 transfected into human embryonic kidney (HEK)293 cells co-immunoprecipitate through binding between the PY motif of PDLIM7 and the second and third WW domains of Nedd4-1 and endogenous PDLIM7 and Nedd4-1 interact in the cytoplasm of differentiated C2C12 myotubes, leading to PDLIM7 ubiquitination. These results identify PDLIM7 as a bona fide skeletal muscle substrate of Nedd4-1 and suggest that this interaction may underlie the progression of skeletal muscle atrophy. This offers a novel therapeutic target that could be potentially used to attenuate muscle atrophy.
authors.affiliation: Keenan Center for Biomedical Research, St Michaels Hospital, Toronto, Ontario, Canada, M5B 1W8.
authors.forename: Robert
authors.initials: R
authors.lastname: D'Cruz
authors.affiliation: Keenan Center for Biomedical Research, St Michaels Hospital, Toronto, Ontario, Canada, M5B 1W8.
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Plant
authors.affiliation: Keenan Center for Biomedical Research, St Michaels Hospital, Toronto, Ontario, Canada, M5B 1W8.
authors.forename: Lesley A
authors.initials: LA
authors.lastname: Pablo
authors.affiliation: Keenan Center for Biomedical Research, St Michaels Hospital, Toronto, Ontario, Canada, M5B 1W8.
authors.forename: Shouzhe
authors.initials: S
authors.lastname: Lin
authors.affiliation: Keenan Center for Biomedical Research, St Michaels Hospital, Toronto, Ontario, Canada, M5B 1W8.
authors.forename: Joshua
authors.initials: J
authors.lastname: Chackowicz
authors.affiliation: Keenan Center for Biomedical Research, St Michaels Hospital, Toronto, Ontario, Canada, M5B 1W8.
authors.forename: Judy
authors.initials: J
authors.lastname: Correa
authors.affiliation: Department of Surgery, McMaster University, Hamilton, Ontario, Canada, L8S 4L8.
authors.forename: James
authors.initials: J
authors.lastname: Bain
authors.affiliation: Keenan Center for Biomedical Research, St Michaels Hospital, Toronto, Ontario, Canada, M5B 1W8 Department of Medicine, St Michaels Hospital, University of Toronto, Toronto, Ontario, Canada, M5B 1W8 jane.batt@utoronto.ca.
authors.forename: Jane
authors.initials: J
authors.lastname: Batt
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D003598:Cytoskeletal Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D056827:Endosomal Sorting Complexes Required for Transport / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D060588:LIM Domain Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000201:enzymology* / Q000378:metabolism; D000075702:Nedd4 Ubiquitin Protein Ligases; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D003598:Cytoskeletal Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; C484381:Pdlim7 protein, mouse; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618483:Nedd4 protein, human; C000618461:Nedd4l protein, mouse; D044767:Ubiquitin-Protein Ligases
keywords: Enigma; PDLIM7; muscle atrophy; skeletal muscle-specific Nedd4-1 knockout mice; ubiquitin–proteasome system