Abstract
BackgroundMutations in myosin chaperones Unc45b and Hsp90aa1.1 as well as in the Unc45b-binding protein Smyd1b impair formation of myofibrils in skeletal muscle and lead to the accumulation of misfolded myosin. The concomitant transcriptional response involves up-regulation of the three genes encoding these proteins, as well as genes involved in muscle development. The transcriptional up-regulation of unc45b, hsp90aa1.1 and smyd1b is specific to zebrafish mutants with myosin folding defects, and is not triggered in other zebrafish myopathy models.ResultsBy dissecting the promoter of unc45b, we identify a Heat shock factor 1 (Hsf1) binding element as a mediator of unc45b up-regulation in myofibers lacking myosin folding proteins. Loss-of-function of Hsf1 abolishes unc45b up-regulation in mutants with defects in myosin folding.ConclusionsTaken together, our data show that skeletal muscle cells respond to defective myosin chaperones with a complex gene program and suggest that this response is mediated by Hsf1 activation.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-015-0825-8) contains supplementary material, which is available to authorized users.
Highlights
Mutations in myosin chaperones Unc45b and Hsp90aa1.1 as well as in the Unc45b-binding protein Smyd1b impair formation of myofibrils in skeletal muscle and lead to the accumulation of misfolded myosin
Up-regulation of myosin chaperones is specific to mutants with myosin folding defects Impaired formation of myofibrils in zebrafish with mutations in the unc45b, hsp90a and smyd1b genes is associated with increased abundance of the transcripts of the three genes in the muscle [1, 9, 13]
We investigated whether the endogenous unc45b gene would be impaired in its response in an unc45b mutant background by knock-down of Heat shock factor 1 (Hsf1)
Summary
Mutations in myosin chaperones Unc45b and Hsp90aa1.1 as well as in the Unc45b-binding protein Smyd1b impair formation of myofibrils in skeletal muscle and lead to the accumulation of misfolded myosin. The transcriptional up-regulation of unc45b, hsp90aa1.1 and smyd1b is specific to zebrafish mutants with myosin folding defects, and is not triggered in other zebrafish myopathy models. Formation of the contractile myofibril of the skeletal muscle is a complex process and involves the correct synthesis, folding and assembly of a huge number of proteins. Auxiliary proteins such as Unc45b or Hsp90aa1.1 (referred to as Hsp90a) contribute to this process by folding the myosin motor domain and organizing the filament structure [1,2,3,4]. It has not been shown to be directly a
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