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J. Biol. Chem., Vol. 281, Issue 37, 26966-26975, September 15, 2006

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Analysis of Properties of Small Heat Shock Protein Hsp25 in MAPK-activated Protein Kinase 2 (MK2)-deficient Cells

MK2-DEPENDENT INSOLUBILIZATION OF Hsp25 OLIGOMERS CORRELATES WITH SUSCEPTIBILITY TO STRESS^*

From the Institute of Biochemistry, Medical School Hannover, Hannover 30625, Germany

Small heat shock proteins (sHsps) exist in dynamic oligomeric complexes and display diverse biological functions ranging from chaperone properties to modulator of apoptosis. So far, the role of stress-dependent phosphorylation of mammalian sHsps for its structure and function has been analyzed by using various phosphorylation site mutants overexpressed in different cell types as well as by non-exclusive inhibitors of the p38 MAPK cascade. Here we investigate the role of phosphorylation of endogenous sHsp in a genetic model lacking the major Hsp25 kinase, the MAP kinase-activated protein kinase MK2. We demonstrate that in MK2-deficient fibroblasts, where no stress-dependent phosphorylation of Hsp25 at Ser⁸⁶ and no in vitro binding to 14-3-3 was detectable, stress-dependent disaggregation of endogenous Hsp25 complexes is impared and kinetics of arsenite-dependent, H₂O₂-dependent, and sublethal heat shock-induced insolubilization of Hsp25 is delayed. Similarly, green fluorescent protein-tagged Hsp25 shows retarded subcellular accumulation into stress granules in MK2-deficient cells after arsenite treatment. Decreased insolubilization of Hsp25 in MK2-deficient cells correlates with increased resistance against arsenite, H₂O₂, and sublethal heat shock treatment and with decreased apoptosis. In contrast, after severe, lethal heat shock MK2-deficient embryonic fibroblasts cells show fast and complete insolubilization of Hsp25 independent of MK2 and no increased stress resistance. Hence, MK2-dependent formation of insoluble stress granules and irreversible cell damage by oxidative stresses and sublethal heat shock correlate and only upon severe, lethal heat shock MK2-independent processes could determine insolubilization of Hsp25 and are more relevant for cellular stress damage.

Received for publication, March 7, 2006 , and in revised form, July 13, 2006.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Medical School Hannover, Institute of Biochemistry, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany. Tel.: 49-511-532-2825; Fax: 49-511-532-2827; E-mail: gaestel.matthias{at}mh-hannover.de.

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