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The recently published review by Dreiza et al. (Cell Stress and Chaperones DOI 10.1007/s12192-0090127-8) dealing with the functional role of HSPB6 in muscle regulation is critically analyzed. Published data indicate that the chaperone-like activity of HSPB6 is comparable with that of HSPB5 and that phosphorylation of HSPB6 does not affect its oligomeric structure. Different hypotheses concerning the molecular mechanisms of HSPB6 action on smooth muscle contraction and on the reorganization of the cytoskeleton are compared, and it is concluded that although HSPB6 is not a genuine actin-binding protein, it can affect the actin cytoskeleton indirectly. Phosphorylated HSPB6 interacts with 14-3-3 and thereby displaces other binding partners of 14-3-3; among them, certain phosphatases, protein kinases, and various actin-binding proteins, which can participate in the reorganization of the actin cytoskeleton. In addition, HSPB6 seems to regulate the activity of certain protein kinases. All of these processes are dependent on HSPB6 phosphorylation which in turn might be regulated by the formation of heterooligomeric complexes of HSPB6 with other small heat shock proteins.
We have read with great interest the recently published mini review by Dreiza et al. (2009). It contains important information on the role of small heat shock protein HSPB6 in the regulation of muscle contraction and the utilization of the short peptide derived from this protein for regulation of muscle tone and cytoskeleton. This review contains a compendium of data of interest to physiologists and medical doctors and combines the achievements of basic science with the demands of practical medicine. However, there are several issues that remain controversial or oversimplified and require brief comments:
The recently published reviews (Fan et al. 2005; Gusev et al. 2005; Dreiza et al. 2009) indicate that HSPB6 is involved in the regulation of many diverse processes such as relaxation of vascular muscle, myocardial contraction, myometrium functioning, platelet aggregation, and apoptosis. In addition, HSPB6 seems to participate in many pathological processes such as asthma, intimal hyperplasia, and insulin resistance. The question of why HSPB6 is so versatile remains unanswered. However, we hypothesize that the versatility of HSPB6 can be explained (at least partly) by its ability to interact with 14-3-3 (Chernik et al. 2007). Binding of phosphorylated HSPB6 to 14-3-3 can induce displacement of certain binding partners of 14-3-3 and among them pro- or antiapoptotic factors, protein kinases, protein phosphatases, and proteins involved in regulation of the actin cytoskeleton. The order and the nature of displaced proteins will be dependent on the abundance and affinity of the client proteins to 14-3-3 and on the availability of phosphorylated HSPB6. The unusual versatility of HSPB6 can also be explained by its direct involvement in the regulation of different protein kinases as was postulated by Fan et al. in recently published papers (Fan et al. 2006, 2008). Both these processes seem to be dependent on HSPB6 phosphorylation, which in turn might be regulated by formation of heterooligomeric complexes of HSPB6 with the other small heat shock proteins (Bukach et al. 2009).
This work was supported by the Russian Foundation for Basic Research.