HSPB7 interacts with dimerized FLNC and its absence results in progressive myopathy in skeletal muscles.

Liang-Yi Juo,Bih-Ying Yang,An-Bang Liu,Yen-Ling Shih,Wern-Chir Liao,Yu-Ting Yan

doi:10.1242/jcs.179887

Abstract

ABSTRACTHSPB7 belongs to the small heat-shock protein (sHSP) family, and its expression is restricted to cardiac and skeletal muscles from embryonic stages to adulthood. Here, we found that skeletal-muscle-specific ablation of the HspB7 does not affect myogenesis during embryonic stages to postnatal day 1 (P1), but causes subsequent postnatal death owing to a respiration defect, with progressive myopathy phenotypes in the diaphragm. Deficiency of HSPB7 in the diaphragm muscle resulted in muscle fibrosis, sarcomere disarray and sarcolemma integrity loss. We identified dimerized filamin C (FLNC) as an interacting partner of HSPB7. Immunofluorescence studies demonstrated that the aggregation and mislocalization of FLNC occurred in the muscle of HspB7 mutant adult mice. Furthermore, the components of dystrophin glycoprotein complex, γ- and δ-sarcoglycan, but not dystrophin, were abnormally upregulated and mislocalized in HSPB7 mutant muscle. Collectively, our findings suggest that HSPB7 is essential for maintaining muscle integrity, which is achieved through its interaction with FLNC, in order to prevent the occurrence and progression of myopathy.

Highlights

The cardiovascular heat-shock protein HSPB7 is a member of the small heat-shock protein family (Krief et al, 1999; Vos et al, 2008)
HSPB7 is expressed in striated muscles We investigated in vivo HSPB7 expression in the skeletal muscle from embryonic stages [embryonic day (E) 14.5] to adulthood
We provided compelling evidence indicating that the loss of HSPB7 function is sufficient to induce the development of a progressive myopathy phenotype associated with myofibrillar disorganization and sarcolemma disruption in mice

Summary

Introduction

The cardiovascular heat-shock protein (cvHsp) HSPB7 is a member of the small heat-shock protein (sHSP or HSPB) family (Krief et al, 1999; Vos et al, 2008). The genes of 10 members of the sHSP family have been identified from the human genome. All sHSPs contain a conserved domain called the α-crystallin domain. SHSPs are molecular ATP-independent chaperones that can store aggregated proteins as folding-competent intermediates, conferring enhanced stress resistance to cells by suppressing the aggregation of denaturing proteins (Sun and MacRae, 2005b). Some sHSPs that are high-molecular-mass complexes dissociate into a small oligomer or a dimer through phosphorylation regulation, preventing the irreversible aggregation of denaturing proteins (Sun and MacRae, 2005a). Several studies have demonstrated that mammalian sHSPs exhibit the ability to interact and/or modulate the structure and dynamics of the cytoskeleton

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