Immense Cellular Implications Associated to Small Stress Proteins Expression: Impacts on Human Pathologies

Abstract

In addition to being potent chaperones that protect cells against the accumulation of unfolded proteins under stress conditions, mammalian small heat shock proteins (small Hsps) regulate many vital cellular processes in normal and pathological cells. Indeed, these Hsps are constitutively expressed in many tissues and show dramatic changes in their levels of expression in most human pathologies. They are characterized by a large spectrum of activities and are particularly active in protein conformational and infl ammatory diseases as well as in cancer pathologies. It is now believed that the immense cellular implications of small Hsps results from their ability to interact, through particular structural changes, with many different client proteins that are subsequently modulated in their activities or half-lifes. Here, we have integrated functionally and structurally the recent data in the literature concerning the interactions of mammalian small Hsps with specifi c clients. Further analysis with geneMANIA software and database confi rmed the incredibly large number of functions associated with these Hsps. The consequences for human pathologies as well as putative therapeutic strategies are discussed, particularly when the expression of small Hsps is harmful (as in some cancer pathologies) or when it appears benefi cial for patients.

Mammalian HspB1 (Hsp27) is a molecular sensor linked to the physiology and environment of the cell

“…The phenomenon is particularly intense in cancer cells where it stimulates their tumorigenic potential Arrigo et al 2007;Ciocca et al 2015;Ciocca et al 2013). Moreover, constitutively expressed HspB1 has recently been discovered to have a large number of apparently unrelated cellular functions that could result, as we recently proposed, of its ability to interact with many different protein partners (Arrigo 2013;Arrigo et al 2015;Arrigo and Gibert 2012, 2013Gibert et al 2012a). Hence, increasing our knowledge of HspB1 structural organization in living cells could help in the understanding of how this protein can chaperone and modulate the activity and/or half-life of so many crucial client polypeptides (Arrigo 2013;Arrigo et al 2015;Arrigo and Gibert 2013).…”

Heat Shock Proteins Promote Cancer: It's a Protection Racket

“…Hsp60, Hsp70, Hsp90 and Hsp110 each utilize ATP binding and hydrolysis to mediate cycles of polypeptide binding, folding and release [5, 7, 10, 11]. The small HSP, Hsp27 is an exception and appears to function in folding reactions by formation of large oligomers that can store proteins in an aggregation-independent state[12]. Lacking an ATPase domain, Hsp27 requires the activity of Hsp70 or Hsp90 to become released from bound client proteins[12].…”

“…The small HSP, Hsp27 is an exception and appears to function in folding reactions by formation of large oligomers that can store proteins in an aggregation-independent state[12]. Lacking an ATPase domain, Hsp27 requires the activity of Hsp70 or Hsp90 to become released from bound client proteins[12]. Hsp110 although possessing abundant protein binding (holdase) activity appears to function largely as a co-chaperone for Hsp70 and a complex of Hsp110-Hsp70-J-domain co-chaperones possess the capacity to refold aggregated proteins[13].…”

“…Within the cell, proteins associated with Hp27 are passed on to Hsp70- co-chaperone complexes. Finally, the Hsp70-bound clients are passed to Hsp90 complexes, which carry out the finishing touches, producing a folded and functional client protein[9, 12]. Inhibition of any of these stages inhibits the folding reaction.…”

“…We have prepared an overall review of the properties of HSPs that may influence the defining traits of cancer. More detailed reviews regarding the mechanisms, in tumor development of HSPs in general[21], Hsp27[12], Hsp70[22], Hsp90 and its inhibitors[23] are available. We have concentrated on Hsp27, Hsp70 and Hsp90 as the majority of reports encountered by us in the literature involved these chaperones.…”