Functional Diversity of Mammalian Small Heat Shock Proteins: A Review

Abstract

The small heat shock proteins (sHSPs), whose molecular weight ranges from 12∼43 kDa, are members of the heat shock protein (HSP) family that are widely found in all organisms. As intracellular stress resistance molecules, sHSPs play an important role in maintaining the homeostasis of the intracellular environment under various stressful conditions. A total of 10 sHSPs have been identified in mammals, sharing conserved α-crystal domains combined with variable N-terminal and C-terminal regions. Unlike large-molecular-weight HSP, sHSPs prevent substrate protein aggregation through an ATP-independent mechanism. In addition to chaperone activity, sHSPs were also shown to suppress apoptosis, ferroptosis, and senescence, promote autophagy, regulate cytoskeletal dynamics, maintain membrane stability, control the direction of cellular differentiation, modulate angiogenesis, and spermatogenesis, as well as attenuate the inflammatory response and reduce oxidative damage. Phosphorylation is the most significant post-translational modification of sHSPs and is usually an indicator of their activation. Furthermore, abnormalities in sHSPs often lead to aggregation of substrate proteins and dysfunction of client proteins, resulting in disease. This paper reviews the various biological functions of sHSPs in mammals, emphasizing the roles of different sHSPs in specific cellular activities. In addition, we discuss the effect of phosphorylation on the function of sHSPs and the association between sHSPs and disease.

Regulation of Epithelial and Endothelial Barriers by Molecular Chaperones

“…HSPBs or small heat shock proteins represent a subfamily of molecular chaperones widely expressed in animals, plants, bacteria, and some viruses [ 139 , 140 ]. In mammals, there are 10 different members of this subfamily (HSPB1 through to HSPB10) that are characterized by either ubiquitous (HSPB1, HSPB5, HSPB6, and HSPB8) or tissue-specific expression [ 139 , 141 ]. Interestingly, only HSPB1, HSPB5, and HSPB8 appear to be inducible by high temperatures and other environmental stressors [ 142 ].…”

“…The anti-aggregation activities of HSPBs most likely underline the cytoprotective functions of these chaperones. Several members of the HSPB family are known to inhibit major cell death pathways, such as apoptosis and ferroptosis, and attenuate the cellular senescence induced by various extracellular stressors [ 139 , 141 , 142 ]. The mechanisms underlying the cytoprotective activities of HSPBs are likely to be complex since these chaperones interact with many client proteins, including crucial kinases, cytoskeletal components, apoptotic proteins, ubiquitin ligases, and inflammatory factors [ 140 , 142 ].…”

“…MAPKAP kinases are downstream effectors of the well-known stress-sensitive p38 kinase, whose activation plays a major role in the phosphorylation of HSPB chaperones in stressed cells. In addition to the p38-MAPKAP cascade, other important protein kinases such as PI3K/AKT, ERK1/2, PKC, PKD, and cAMP/PKA have been shown to phosphorylate different HSPBs [ 139 , 145 ]. Phosphorylation is known to modulate HSPB oligomerization and activity.…”

“…Molecular mechanisms underlying the described effects of HSPB chaperones on epithelial and endothelial junctions remain poorly investigated and likely involve the regulation of different cellular structures and processes. Functions of HSPBs can be divided into three broad categories: prevention of protein aggregation, regulation of the redox status of the cell, and controlling the cytoskeletal architecture and dynamics [ 139 , 140 , 141 ]. While no direct evidence demonstrates that the first two action modes are essential for HSPB-dependent tissue barrier regulation, accumulating data support the importance of actin cytoskeletal remodeling.…”