Oculopharyngeal muscular dystrophy mutations link the RNA-binding protein HNRNPQ to autophagosome biogenesis.
Hasan IshtayehMargarita GalvesTania T BarnatanYevgeny BerdichevskyFatima Amer-SarsourMetsada Pasmanik-ChorItzhak BravermanSergiu C BlumenAvraham AshkenaziPublished in: Aging cell (2023)
Autophagy is an intracellular degradative process with an important role in cellular homeostasis. Here, we show that the RNA binding protein (RBP), heterogeneous nuclear ribonucleoprotein Q (HNRNPQ)/SYNCRIP is required to stimulate early events in autophagosome biogenesis, in particular the induction of VPS34 kinase by ULK1-mediated beclin 1 phosphorylation. The RBPs HNRNPQ and poly(A) binding protein nuclear 1 (PABPN1) form a regulatory network that controls the turnover of distinct autophagy-related (ATG) proteins. We also show that oculopharyngeal muscular dystrophy (OPMD) mutations engender a switch from autophagosome stimulation to autophagosome inhibition by impairing PABPN1 and HNRNPQ control of the level of ULK1. The overexpression of HNRNPQ in OPMD patient-derived cells rescues the defective autophagy in these cells. Our data reveal a regulatory mechanism of autophagy induction that is compromised by PABPN1 disease mutations, and may thus further contribute to their deleterious effects.
Keyphrases
- muscular dystrophy
- binding protein
- induced apoptosis
- endoplasmic reticulum stress
- cell death
- cell cycle arrest
- signaling pathway
- oxidative stress
- duchenne muscular dystrophy
- cell proliferation
- protein kinase
- pi k akt
- electronic health record
- mouse model
- reactive oxygen species
- dna methylation
- bone mineral density
- big data
- deep learning
- postmenopausal women
- nucleic acid