The kinase domain of titin controls muscle gene expression and protein turnover

被引:437
作者
Lange, S
Xiang, FQ
Yakovenko, A
Vihola, A
Hackman, P
Rostkova, E
Kristensen, J
Brandmeier, B
Franzen, G
Hedberg, B
Gunnarsson, LG
Hughes, SM
Marchand, S
Sejersen, T
Richard, I
Edström, L
Ehler, E
Udd, B
Gautel, M [1 ]
机构
[1] Univ Helsinki, Folkhalsen Inst Genet, Biomedicum, FIN-00290 Helsinki, Finland
[2] Univ Helsinki, Dept Med Genet, Biomedicum, FIN-00290 Helsinki, Finland
[3] Kings Coll London, Randall Div, London SE1 1UL, England
[4] Kings Coll London, Div Cardiovasc, London SE1 1UL, England
[5] ETH Honggerberg, Inst Cell Biol, CH-8093 Zurich, Switzerland
[6] Karolinska Inst, Karolinska Hosp, Dept Clin Neurosci, S-17176 Stockholm, Sweden
[7] Orebro Univ Hosp, Dept Environm Med, S-70185 Orebro, Sweden
[8] Genethon, CNRS, UMR 8115, F-91000 Evry, France
[9] Astrid Lindgren Childrens Hosp, Dept Woman & Child Hlth, Neuropediat Unit, S-17176 Stockholm, Sweden
[10] Vasa Cent Hosp, Dept Neurol, Vaasa 65130, Finland
[11] Tampere Univ Hosp, Dept Neurol, Tampere 33520, Finland
基金
英国医学研究理事会;
关键词
D O I
10.1126/science.1110463
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
The giant sarcomeric protein titin contains a protein kinase domain (TK) ideally positioned to sense mechanical load. We identified a signaling complex where TK interacts with the zinc-finger protein nbr1 through a mechanically inducible conformation. Nbr1 targets the ubiquitin-associated p62/SQSTM1 to sarcomeres, and p62 in turn interacts with MuRF2, a muscle-specific RING-B-box E3 ligase and ligand of the transactivation domain of the serum response transcription factor (SRF). Nuclear translocation of MuRF2 was induced by mechanical inactivity and caused reduction of nuclear SRF and repression of transcription. A human mutation in the titin,protein kinase domain causes hereditary muscle disease by disrupting this pathway.
引用
收藏
页码:1599 / 1603
页数:5
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