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UBA1 knockdown dysregulates UBA1-sensitive proteins and impairs muscle function in models of spinal muscular atrophy X-linked 2.

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Τίτλος: UBA1 knockdown dysregulates UBA1-sensitive proteins and impairs muscle function in models of spinal muscular atrophy X-linked 2.
Συγγραφείς: Curley M; Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Graca FA; Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Stephan A; Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Wang W; Center for Proteomics and Metabolomics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Pagala VR; Center for Proteomics and Metabolomics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Wang YD; Department of Cellular and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., High AA; Center for Proteomics and Metabolomics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Demontis F; Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Πηγή: Disease models & mechanisms [Dis Model Mech] 2026 Aug 01; Vol. 19 (8). Date of Electronic Publication: 2026 Aug 26.
Τύπος έκδοσης: Journal Article
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: Company of Biologists Ltd Country of Publication: England NLM ID: 101483332 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1754-8411 (Electronic) Linking ISSN: 17548403 NLM ISO Abbreviation: Dis Model Mech Subsets: MEDLINE
Imprint Name(s): Original Publication: Cambridge : Company of Biologists Ltd., c2008-
Ιατρικοί όροι (MeSH): Ubiquitin-Activating Enzymes*/metabolism , Ubiquitin-Activating Enzymes*/genetics , Muscular Atrophy, Spinal*/physiopathology , Muscular Atrophy, Spinal*/genetics , Muscular Atrophy, Spinal*/metabolism , Muscular Atrophy, Spinal*/pathology , Muscle, Skeletal*/physiopathology , Muscle, Skeletal*/pathology , Gene Knockdown Techniques*, Drosophila melanogaster/metabolism ; Drosophila melanogaster/genetics ; Animals ; Ubiquitination ; Disease Models, Animal ; RNA Interference ; Humans
Περίληψη: UBA1 is the primary ubiquitin-activating enzyme that initiates ubiquitination, which regulates protein function and turnover. Although UBA1 loss is cell lethal, silent mutations that reduce UBA1 mRNA levels cause spinal muscular atrophy X-linked 2 (SMAX2), a disorder marked by skeletal muscle weakness and wasting. However, it remains unexplored how UBA1 impacts the muscle proteome, and whether muscle weakness can arise from reducing UBA1 function solely in skeletal muscle. Here, we examined Drosophila and mice with muscle-targeted UBA1 knockdown and found that this intervention reduced protein ubiquitination, muscle function and lifespan. Integrated transcriptomic and proteomic analyses indicated that a limited set of proteins is modulated post-transcriptionally by Uba1 RNA interference (Uba1RNAi), suggesting that these UBA1-sensitive proteins rely on optimal UBA1 levels for degradation (Uba1RNAi-upregulated proteins) and stability (Uba1RNAi-downregulated proteins). Therefore, despite the general function of UBA1 in ubiquitination, UBA1 knockdown alters the levels of relatively few critical proteins, which may contribute to muscle weakness and SMAX2 pathogenesis. Moreover, although SMAX2-linked UBA1 mutations occur ubiquitously, experimental reduction of UBA1 function solely in skeletal muscle recapitulates key disease aspects, highlighting a possible muscle-centric origin of SMAX2.
(© 2026. Published by The Company of Biologists.)
Competing Interests: Competing interests The authors declare no competing or financial interests.
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Grant Information: R01 AG075869 United States AG NIA NIH HHS; R01AG075869 United States AG NIA NIH HHS; American Lebanese Syrian Associated Charities
Contributed Indexing: Keywords: Muscle function; Proteostasis; SMAX2; Skeletal muscle; UBA1; Ubiquitination
Substance Nomenclature: EC 6.2.1.45 (Ubiquitin-Activating Enzymes)
Entry Date(s): Date Created: 20260706 Date Completed: 20260826 Latest Revision: 20260918
Update Code: 20260918
PubMed Central ID: PMC13580589
DOI: 10.1242/dmm.052935
PMID: 42402962
Βάση Δεδομένων: MEDLINE
Περιγραφή
ISSN:1754-8411
DOI:10.1242/dmm.052935