A novel feed-forward loop between ARIH2 E3-ligase and PABPN1 regulates aging-associated muscle degeneration.
Alanine expansion mutations in poly(A)-binding protein nuclear 1 (PABPN1) cause muscle weakness in the late-onset disorder oculopharyngeal muscular dystrophy. In affected muscles, expanded PABPN1 forms nuclear aggregates, depleting levels of soluble PABPN1 and inducing a genome-wide shift from distal to proximal polyadenylation site usage. PABPN1 protein accumulation is regulated by the ubiquitin proteasome system, which is highly dysregulated in oculopharyngeal muscular dystrophy. We show that ARIH2 E3-ligase regulates PABPN1 protein accumulation and aggregation. Levels of ARIH2 mRNA are regulated by PABPN1 via proximal polyadenylation site usage. We demonstrate that masking the proximal polyadenylation site in ARIH2 3' untranslated region by antisense oligonucleotides elevates the expression of ARIH2 and PABPN1 and restores myogenic defects that are induced by ARIH2 or PABPN1 down-regulation in cell culture. In vivo ARIH2 mRNA levels significantly decrease from midlife in vastus lateralis muscles and highly correlate with muscle degeneration. We suggest that the expression of both genes is maintained by a feed-forward loop between mRNA stability regulated by PABPN1 and protein turnover regulated by ARIH2.
Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands. Electronic address: v.raz@lumc.nl.
Vered
V
Raz
Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Hellen
H
Buijze
Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands.
Yotam
Y
Raz
Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Nisha
N
Verwey
Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Seyed Yahya
SY
Anvar
Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Annemieke
A
Aartsma-Rus
Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Silvère M
SM
van der Maarel
D000375:Aging / Q000473:pathology* / Q000502:physiology; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology*; D039141:Muscular Dystrophy, Oculopharyngeal / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D039122:Poly(A)-Binding Protein I / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
C576588:PABPN1 protein, human; D039122:Poly(A)-Binding Protein I; C506696:ARIH2 protein, human; D044767:Ubiquitin-Protein Ligases