Centre for Neuroscience and Nanotechnology, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41125, Modena, Italy.
Max Planck Institute of Immunobiology and Epigenetics, 79108, Freiburg, Germany.
Cell Death Dis. 2021 May 6;12(5):452. doi: 10.1038/s41419-021-03737-1.
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.
调控肌肉细胞分化的关键事件之一是将核膜层 Lamina B 受体（LBR）连接替换为核膜层 Lamina A/C（LMNA）连接，以重塑转录并诱导分化特异性基因。在这里，我们报告说，肌肉特异性伴侣蛋白 HSPB3 对 LBR 连接的定位和活性至关重要，并且 HSPB3 的耗竭会阻止肌肉细胞分化。我们进一步表明，HSPB3 在核质中与 LBR 结合，并使其保持动态状态，从而促进肌源性基因的转录，包括重塑细胞外基质的基因。值得注意的是，HSPB3 的过表达本身足以诱导两种人类肌肉细胞系 LHCNM2 细胞和横纹肌肉瘤细胞的分化。我们还表明，来自具有染色质改变和肌纤维紊乱的肌病患者的突变型 R116P-HSPB3 形成核聚集体，使 LBR 固定。我们发现 R116P-HSPB3 无法诱导成肌细胞分化，而是激活未折叠蛋白反应。我们提出 HSPB3 是一种专门参与肌肉细胞分化的伴侣蛋白，功能失调的 HSPB3 通过使 LBR 失活而导致神经肌肉疾病。
