Constitutively expressed small heat shock protein HspB1 regulates many fundamental cellular processes and plays major roles in many human pathological diseases. In that regard, this chaperone has a huge number of apparently unrelated functions that appear linked to its ability to recognize many client polypeptides that are subsequently modified in their activity and/or half-life. A major parameter to understand how HspB1 is dedicated to interact with particular clients in defined cellular conditions relates to its complex oligomerization and phosphorylation properties. Indeed, HspB1 structural organization displays dynamic and complex rearrangements in response to changes in the cellular environment or when the cell physiology is modified. These structural modifications probably reflect the formation of structural platforms aimed at recognizing specific client polypeptides. Here, I have reviewed data from the literature and re-analyzed my own studies to describe and discuss these fascinating changes in HspB1 structural organization.

Human small heat shock proteins are molecular chaperones that regulate fundamental cellular processes in normal unstressed cells as well as in many cancer cells where they are over-expressed. These proteins are characterized by cell physiology dependent changes in their oligomerization and phosphorylation status. These structural changes allow them to interact with many different client proteins that subsequently display modified activity and/or half-life. Nowdays, the protein interactomes of small Hsps are under intense investigations and will represent, when completed, key parameters to elaborate therapeutic strategies aimed at modulating the functions of these chaperones. Here, we have analyzed the potential pro-cancerous roles of several client proteins that have been described so far to interact with HspB1 (Hsp27) and its close members HspB5 (αB-crystallin) and HspB4 (αA-crystallin).

Human HspB1 (Hsp27), a molecular chaperone bearing tumorigenic and metastatic roles, is characterized by its dynamic phosphorylation and heterogenous oligomerization in response to changes in cell physiology. The phenomenon is particularly intense and specific when cells are exposed to different death inducers. This favors the hypothesis that the structural organization of HspB1 acts as a sensor which, through reversible modifications, allows cells to adapt and/or mount a protective response. A large number of HspB1 interacting partners have already been described in the literature. Specific changes in oligomerphosphorylation organization may therefore allow HspB1 to interact with the more appropriate polypeptides and to subsequently modulate their folding/activity and/or half-life. This could indirectly link HspB1 to multiple cellular functions and could explain the apparently unrelated effects associated to its over- or underexpression. In cancer, HspB1 is tumorigenic, stimulates metastasis and provide cancer cells with resistance to many anti-cancer drugs, so compounds aimed at disrupting HspB1 deleterious pro-cancer activity are actively looked for. One example, is brivudine that impairs HspB1 ability to recognize pathological protein substrates and appears as a promising anti-cancer drug. Similarly, we have observed that peptide aptamers that specifically interfere with HspB1 structural organization reduced its anti-apoptotic and tumorigenic activities. We propose that, in addition to RNA interference approaches, the tumorigenic activity of HspB1 could be inhibited by altering HspB1 structural organization and consequently its interaction with inappropriate procancerous polypeptide partners. Hence, developping HspB1 structure-based interfering strategies could lead to new anti-cancer drugs discovery.

Human HSP27 (HSPB1) is a molecular chaperone sensor which, through dynamic changes in its phosphorylation and oligomerization, allows cells to adapt to changes in their physiology and/or mount a protective response to injuries. In pathological conditions, the high level of HSPB1 expression can either be beneficial, such as in diseases characterized by cellular degenerations, or be malignant in cancer cells where it promotes tumourigenesis, metastasis and anti-cancer drug resistance. Structural changes allow HSPB1 to interact with specific client protein partners in order to modulate their folding/activity and/or half-life. Therefore, the search is open for therapeutic compounds aimed at either down- or upregulating HSPB1 activity. In this respect, we have previously described two peptide aptamers (PA11 and PA50) that specifically interact with HSPB1 small oligomers and decrease its anti-apoptotic and tumourigenic activities. A novel analysis of the different HSPB1-interacting aptamers that were isolated earlier revealed that one aptamer (PA23) has the intriguing ability to stimulate the protective activity of HSPB1. We show here that this aptamer abolishes the dominant negative effect induced by the R120G mutant of αB-crystallin (HSPB5) by disrupting its interaction with HSPB1. Hence, developing structure-based interfering strategies could lead to the discovery of HSPB1-based therapeutic drugs.