HSPB8

HSPB8 (heat shock protein beta-8, also called HSP22, H11 kinase, E2IG1 or alpha-crystallin C chain) is a member of the small heat shock protein (sHSP / HSP20, alpha-crystallin domain) family, predominantly expressed in skeletal muscle and heart. It is an ATP-independent molecular chaperone (holdase) that binds aggregation-prone and stress-destabilized client proteins. Its central role is in chaperone-assisted selective autophagy (CASA), where together with the co-chaperone BAG3, the Hsp70 chaperones HSPA8/HSC70 and HSPA1A, and the ubiquitin ligase STUB1/CHIP, HSPB8 routes damaged clients (e.g. filamin and polyglutamine-expanded proteins) for autophagic degradation via p62/SQSTM1, a process essential for maintenance of the muscle Z-disk under mechanical stress. HSPB8 forms homodimers and hetero-oligomers with other small HSPs (HSPB1, HSPB2, HSPB7) and DNAJB6. Despite an early report of protein kinase activity, recombinant HSPB8 lacks detectable kinase activity. It localizes to the cytoplasm and nucleus and translocates to nuclear foci during heat shock. Dominant variants (notably at the K141 hot spot) cause distal hereditary motor neuropathy, Charcot-Marie-Tooth disease type 2L, and myofibrillar/rimmed-vacuole myopathy.

Disorders

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