The problem of protein kinase activity of small heat shock protein Hsp22 (H11 or HspB8)
ABSTRACT The recently described protein denoted H11, Hsp22 or HspB8 seems to participate in regulation of proliferation, apoptosis, and cardiac hypertrophy. Mutation of Hsp22 causes distal motor neuropathy. Multitude action of Hsp22 is supposed to be due to its protein kinase and/or chaperone-like activities. There are many indirect evidences indicating that Hsp22 possesses intrinsic protein kinase activity. However, low homology to protein kinases, low extent of autophosphorylation, lack of significant protein kinase activity with commonly used substrates, and lack of information on stoichiometry, kinetics, and substrate specificity make the existence of intrinsic protein kinase activity of Hsp22 questionable. It is supposed that protein kinase activity ascribed to Hsp22 is due to contaminating protein kinases. Hsp22 is highly homologous to small heat shock proteins and effectively prevents aggregation of denatured protein both in vitro and in vivo. Therefore, it is supposed that chaperone-like activity is of great importance for Hsp22 functioning.
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ABSTRACT: Modern classification of the family of human small heat shock proteins (the so-called HSPB) is presented, and the structure and properties of three members of this family are analyzed in detail. Ubiquitously expressed HSPB1 (HSP27) is involved in the control of protein folding and, when mutated, plays a significant role in the development of certain neurodegenerative disorders. HSPB1 directly or indirectly participates in the regulation of apoptosis, protects the cell against oxidative stress, and is involved in the regulation of the cytoskeleton. HSPB6 (HSP20) also possesses chaperone-like activity, is involved in regulation of smooth muscle contraction, has pronounced cardioprotective activity, and seems to participate in insulin-dependent regulation of muscle metabolism. HSPB8 (HSP22) prevents accumulation of aggregated proteins in the cell and participates in the regulation of proteolysis of unfolded proteins. HSPB8 also seems to be directly or indirectly involved in regulation of apoptosis and carcinogenesis, contributes to cardiac cell hypertrophy and survival and, when mutated, might be involved in development of neurodegenerative diseases. All small heat shock proteins play important "housekeeping" roles and regulate many vital processes; therefore, they are considered as attractive therapeutic targets.Physiological Reviews 10/2011; 91(4):1123-59. DOI:10.1152/physrev.00023.2010 · 29.04 Impact Factor
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ABSTRACT: Although short-term disuse does not result in measurable muscle atrophy, studies suggest that molecular changes associated with protein degradation may be initiated within days of the onset of a disuse stimulus. We examined the global gene expression patterns in sedentary men (n = 7, mean age ± SD = 22.1 ± 3.7 yr) following 48 h unloading (UL) via unilateral lower limb suspension and 24 h reloading (RL). Biopsy samples of the left vastus lateralis muscle were collected at baseline, 48 h UL, and 24 h RL. Expression changes were measured by microarray and gene clustering; identification of enriched functions and canonical pathways were performed using the Database for Annotation, Visualization and Integrated Discovery (DAVID) and Ingenuity Pathway Analysis (IPA). Four genes were validated with quantitative RT-PCR (qRT-PCR), and protein levels were measured with Western blot. Of the upregulated genes after UL, the most enriched functional group and highest ranked canonical pathway were related to protein ubiquitination. The oxidative stress response pathway was the second highest ranked canonical pathway. Of the downregulated genes, functions related to mitochondrial metabolism were the most highly enriched. In general, gene expression patterns following UL persisted following RL. qRT-PCR confirmed increases in mRNA for ubiquitin proteasome pathway-related E3 ligase Atrogin1 (but not accompanying increases in protein products) and stress response gene heme oxygenase-1 (HMOX, which showed a trend toward increases in protein products at 48 h UL) as well as extracellular matrix (ECM) component COL4A3. The gene expression patterns were not reversed on RL, suggesting that molecular responses to short-term periods of skeletal muscle inactivity may persist after activity resumes.Journal of Applied Physiology 11/2010; 109(5):1404-15. DOI:10.1152/japplphysiol.00444.2010 · 3.43 Impact Factor
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ABSTRACT: Aggregation of mutated proteins is a hallmark of many neurodegenerative disorders, including Huntington disease. We previously reported that overexpression of the HspB8.Bag3 chaperone complex suppresses mutated huntingtin aggregation via autophagy. Classically, HspB proteins are thought to act as ATP-independent molecular chaperones that can bind unfolded proteins and facilitate their processing via the help of ATP-dependent chaperones such as the Hsp70 machine, in which Bag3 may act as a molecular link between HspB, Hsp70, and the ubiquitin ligases. However, here we show that HspB8 and Bag3 act in a non-canonical manner unrelated to the classical chaperone model. Rather, HspB8 and Bag3 induce the phosphorylation of the alpha-subunit of the translation initiator factor eIF2, which in turn causes a translational shut-down and stimulates autophagy. This function of HspB8.Bag3 does not require Hsp70 and also targets fully folded substrates. HspB8.Bag3 activity was independent of the endoplasmic reticulum (ER) stress kinase PERK, demonstrating that its action is unrelated to ER stress and suggesting that it activates stress-mediated translational arrest and autophagy through a novel pathway.Journal of Biological Chemistry 02/2009; 284(9):5523-32. DOI:10.1074/jbc.M807440200 · 4.60 Impact Factor