Exploring the multifaceted roles of heat shock protein B8 (HSPB8) in diseases

•HSPB8 tends to form small-molecular-mass oligomers and possesses a substrate dependent chaperone-like activity.•HSPB8 cooperates with BAG3 to stimulate the autophagic flux and to target damaged clients to autophagy.•Mutations within the crystallin domain of HSPB8 contribute to the development of some kinds of motor neuropathy.•Multiple protein-protein interactions form the basis for the capability of HSPB8 to provide a plethora of different cellular functions.•HSPB8 may promote cell survival against ischemia/reperfusion injury by a synergistic effect of diverse signaling pathways. HSPB8 is a member of ubiquitous small heat shock protein (sHSP) family, whose expression is induced in response to a wide variety of unfavorable physiological and environmental conditions. Investigation of HSPB8 structure indicated that HSPB8 belongs to the group of so-called intrinsically disordered proteins and possesses a highly flexible structure. Unlike most other sHSPs, HSPB8 tends to form small-molecular-mass oligomers and exhibits substrate-dependent chaperone activity. In cooperation with BAG3, the chaperone activity of HSPB8 was reported to be involved in the delivery of misfolded proteins to the autophagy machinery. Through this way, HSPB8 interferes with pathological processes leading to neurodegenerative diseases. Accordingly, published studies have identified genetic links between mutations of HSPB8 and some kind of neuromuscular diseases, further supporting its important role in neurodegenerative disorders. In addition to their anti-aggregation properties, HSPB8 is indicated to interact with a wide range of client proteins, modulating their maturations and activities, and therefore, regulates a large repertoire of cellular functions, including apoptosis, proliferation, inflammation and etc. As a result, HSPB8 has key roles in cancer biology, autoimmune diseases, cardiac diseases and cerebral vascular diseases.