Titin kinase ubiquitination aligns autophagy receptors with mechanical signals in the sarcomere.
X-ray crystallography
cellular signalling
mechanotransduction
steered molecular dynamics simulations
ubiquitination
Journal
EMBO reports
ISSN: 1469-3178
Titre abrégé: EMBO Rep
Pays: England
ID NLM: 100963049
Informations de publication
Date de publication:
05 10 2021
05 10 2021
Historique:
revised:
07
07
2021
received:
28
02
2019
accepted:
19
07
2021
pubmed:
18
8
2021
medline:
11
3
2022
entrez:
17
8
2021
Statut:
ppublish
Résumé
Striated muscle undergoes remodelling in response to mechanical and physiological stress, but little is known about the integration of such varied signals in the myofibril. The interaction of the elastic kinase region from sarcomeric titin (A168-M1) with the autophagy receptors Nbr1/p62 and MuRF E3 ubiquitin ligases is well suited to link mechanosensing with the trophic response of the myofibril. To investigate the mechanisms of signal cross-talk at this titin node, we elucidated its 3D structure, analysed its response to stretch using steered molecular dynamics simulations and explored its functional relation to MuRF1 and Nbr1/p62 using cellular assays. We found that MuRF1-mediated ubiquitination of titin kinase promotes its scaffolding of Nbr1/p62 and that the process can be dynamically down-regulated by the mechanical unfolding of a linker sequence joining titin kinase with the MuRF1 receptor site in titin. We propose that titin ubiquitination is sensitive to the mechanical state of the sarcomere, the regulation of sarcomere targeting by Nbr1/p62 being a functional outcome. We conclude that MuRF1/Titin Kinase/Nbr1/p62 constitutes a distinct assembly that predictably promotes sarcomere breakdown in inactive muscle.
Identifiants
pubmed: 34402565
doi: 10.15252/embr.201948018
pmc: PMC8490993
doi:
Substances chimiques
Connectin
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e48018Subventions
Organisme : NINDS NIH HHS
ID : P30 NS047101
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL137957
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL144872
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL155826
Pays : United States
Informations de copyright
© 2021 The Authors. Published under the terms of the CC BY 4.0 license.
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