title: Unveiling the degradative route of the V247M α-sarcoglycan mutant responsible for LGMD-2D.
abstract: Many membrane and secretory proteins that fail to pass quality control in the endoplasmic reticulum (ER) are dislocated into the cytosol and degraded by the proteasome. In applying rigid rules, however, quality control sometimes discharges proteins that, even though defective, retain their function. The unnecessary removal of such proteins represents the pathogenetic hallmark of diverse genetic diseases, in the case of ΔF508 mutant of cystic fibrosis transmembrane conductance regulator being probably the best known example. Recently, the inappropriate proteasomal degradation of skeletal muscle sarcoglycans (α, β, γ and δ) with missense mutation has been proposed to be at the bases of mild-to-severe forms of limb girdle muscular dystrophy (LGMD) known as type 2D, 2E, 2C and 2F, respectively. The quality control pathway responsible for sarcoglycan mutant disposal, however, is so far unexplored. Here we reveal key components of the degradative route of V247M α-sarcoglycan mutant, the second most frequently reported mutation in LGMD-2D. The disclosure of the pathway, which is led by the E3 ligases HRD1 and RFP2, permits to identify new potential druggable targets of a disease for which no effective therapy is at present available. Notably, we show that the pharmacological inhibition of HRD1 activity rescues the expression of V247-α-sarcoglycan both in a heterologous cell model and in myotubes derived from a LGMD-2D patient carrying the L31P/V247M mutations. This represents the first evidence that the activity of E3 ligases, the enzymes in charge of mutant fate, can be eligible for drug interventions to treat sarcoglycanopathy.
authors.affiliation: Department of Biomedical Sciences and.
authors.forename: Elisa
authors.initials: E
authors.lastname: Bianchini
authors.affiliation: Department of Neurosciences, University of Padova, Padova 35131, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Fanin
authors.affiliation: Institut de Myologie, UPMC UM76, INSERM U974, CNRS UMR 7215, Paris 6, France.
authors.forename: Kamel
authors.initials: K
authors.lastname: Mamchaoui
authors.affiliation: Institute of Neuroscience, Consiglio Nazionale delle Ricerche, Padova 35131, Italy.
authors.forename: Romeo
authors.initials: R
authors.lastname: Betto
authors.affiliation: Department of Biomedical Sciences and dorianna.sandona@unipd.it.
authors.forename: Dorianna
authors.initials: D
authors.lastname: Sandonà
mesh_terms: D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000473:pathology; D020125:Mutation, Missense; D058088:Sarcoglycanopathies / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D049031:Sarcoglycans / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D049031:Sarcoglycans; C112217:TRIM13 protein, human; D025521:Tumor Suppressor Proteins; C482345:SYVN1 protein, human; D044767:Ubiquitin-Protein Ligases