Small heat-shock protein HSPB3 promotes myogenesis by regulating the lamin B receptor

Abstract

One of the critical events that regulates muscle cell differentiation is the replacement of the lamin B receptor (LBR)-tether with the lamin A/C (LMNA)-tether to remodel transcription and induce differentiation-specific genes. Here, we report that localization and activity of the LBR-tether are crucially dependent on the muscle-specific chaperone HSPB3 and that depletion of HSPB3 prevents muscle cell differentiation. We further show that HSPB3 binds to LBR in the nucleoplasm and maintains it in a dynamic state, thus promoting the transcription of myogenic genes, including the genes to remodel the extracellular matrix. Remarkably, HSPB3 overexpression alone is sufficient to induce the differentiation of two human muscle cell lines, LHCNM2 cells, and rhabdomyosarcoma cells. We also show that mutant R116P-HSPB3 from a myopathy patient with chromatin alterations and muscle fiber disorganization, forms nuclear aggregates that immobilize LBR. We find that R116P-HSPB3 is unable to induce myoblast differentiation and instead activates the unfolded protein response. We propose that HSPB3 is a specialized chaperone engaged in muscle cell differentiation and that dysfunctional HSPB3 causes neuromuscular disease by deregulating LBR.

HLH-1 Modulates Muscle Proteostasis During Caenorhabditis elegans Larval Development

“…MyoD/HLH-1 can regulate chaperone expression during muscle differentiation ( Sugiyama et al, 2000 ; Bar-Lavan et al, 2016b ; Echeverria et al, 2016 ; Tiago et al, 2021 ). To ask whether HLH-1 also regulates chaperones’ expression during larval development, we examined the expression of chaperones that are hlh-1 -dependent or hlh-1 -independent.…”

“…While it is still an open question how chaperone expression is regulated in a tissue-specific manner, a role for differentiation transcription factors that establish the cell-specific proteome in defining the chaperone network is well-established ( Nisaa and Ben-Zvi, 2021 ). One well-characterized example is the role of the myogenic transcription factor, MyoD, and its’ Caenorhabditis elegans ortholog, HLH-1 ( Fukushige and Krause, 2005 ), in regulating chaperone expression during muscle differentiation ( Sugiyama et al, 2000 ; Bar-Lavan et al, 2016b ; Echeverria et al, 2016 ; Tiago et al, 2021 ).…”

Insights on Human Small Heat Shock Proteins and Their Alterations in Diseases

“…In C2C12 myoblasts, like HSPB2, HSPB3 is expressed with differentiation (Sugiyama et al, 2000). Indeed, HSPB3 gene presents a MyoDresponsive region and HSPB3 overexpression induces myoblasts differentiation (Tiago et al, 2021). Instead, HSPB3 expression in the nervous system is moderate and varies during development.…”

“…HSPB3 is found in glial cells, in MNs and in sensory neurons (La Padula et al, 2016). HSPB3 localizes in the cytoplasm and associates to cytoskeletal components, e.g., actin bundles and NFs, but also mitochondrial membrane and nuclear envelope (La Padula et al, 2016;Tiago et al, 2021). HSPB3 is upregulated upon proteotoxic stress but not upon thermal stress.…”

“…In cells, the HSPB3 R116P mutant, by losing the ability to bind HSPB2, is not able to regulate the typical HSPB2 nucleuscytoplasm distribution and thus, associates to the abnormal HSPB2 nuclear LLPS (Morelli et al, 2017b). Another HSPB3 R116P pathogenic mechanism relies on its intranuclear aggregation, which results in HSPB3 WT sequestration and deregulation of transcription processes (Morelli et al, 2017b;Tiago et al, 2021). Instead, the HSPB3 Y118H mutation has been described in one CMT patient with a family history of disease.…”