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UID:946@biology.technion.ac.il

DTSTART;TZID=Asia/Jerusalem:20210303T130000

DTEND;TZID=Asia/Jerusalem:20210303T140000

DTSTAMP:20210802T125904Z

URL:https://biology.technion.ac.il/en/seminars/phd-graduate-seminar-dina-a
 weida-2/

SUMMARY:PhD Graduate Seminar-Dina Aweida [No Categories]
DESCRIPTION:Location:   \n Affiliation: \n Host:\n An ordered loss ofdesmin
 filaments precedesand promotes muscle atrophyMyofibril breakdown is a hall
 markof muscle wasting and an inevitable sequel of aging and disease. The d
 esmincytoskeleton is critical for skeletal muscle architecture and functio
 n\, and itsdepolymerization is required for myofibril loss and atrophy. We
  uncovered thesequence of events leading to desmin loss\, which is activat
 ed byphosphorylation. We developed a mass spectrometry-based kinase-trap a
 ssay andidentified glycogen synthase kinase 3-b (GSK3-b) as responsible fo
 r desmin phosphorylation. GSK3-b inhibition in mouse muscle prevented desm
 in phosphorylationand depolymerization\, and blocked atrophy upon fasting 
 or denervation. Hence\,GSK3-b represents a novel drug target to prevent my
 ofibril breakdownand atrophy. Phosphorylation by GSK3-b mediatedthe subseq
 uent cleavage and depolymerization of desmin filaments by the Ca2+-specifi
 cprotease\, calpain-1\, when cytosolic Ca2+ levels rose. Consistently\,cal
 pain-1 downregulation prevented loss of phosphorylated desmin and blockedm
 yofibril breakdown and atrophy. Intriguingly\, the depolymerization of des
 minfilament is facilitated by an understudied protein complex\, the AAA-AT
 Pase\,Atad1. Atad1 bound phosphorylated desmin filaments\, and together wi
 th its two previouslyunidentified co-factors\, PLAA and Ubxn4\, promoted d
 esmin filament solubilizationand loss. Our studies uncovered a cooperative
  role for Atad1 and calpain-1 inpromoting desmin solubilization and loss\,
  because downregulation of both genesin atrophying muscles had an additive
  beneficial effect on desmin filaments andoverall proteolysis. In addition
 \, cleavage of desmin filaments by calpain-1 invitro was more efficient in
  the presence of Atad1. Therefore\, we propose the“Pull and cut” mecha
 nism\, in which Atad1 and calpain-1 cooperate to facilitatedesmin loss in 
 atrophy. 

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