MKBP, A NOVEL MEMBER OF THE SMALL HEAT-SHOCK-PROTEIN FAMILY, BINDS AND ACTIVATES THE MYOTONIC-DYSTROPHY PROTEIN-KINASE

Muscle cells are frequently subjected to severe conditions caused by h eat, oxidative, and mechanical stresses, The small heat shock proteins (sHSPs) such as alpha B-crystallin and HSP27, which are highly expres sed in muscle cells, have been suggested to play roles in maintaining myofibrillar integrity against such stresses. Here, we identified a no vel member of the sHSP family that associates specifically with myoton ic dystrophy protein kinase (DMPK). This DMPK-binding protein, MKBP, s hows a unique nature compared with other known sHSPs: (a) In muscle cy tosol, MKBP exists as an oligomeric complex separate from the complex formed by alpha B-crystallin and HSP27. (b) The expression of MKBP is not induced by heat shock, although it shows the characteristic early response of redistribution to the insoluble fraction like other sHSPs, Immunohistochemical analysis of skeletal muscle cells shows that MKBP localizes to the cross sections of individual myofibrils at the Z-mem brane as well as the neuromuscular junction, where DMPK has been sugge sted to be concentrated, In vitro, MKBP enhances the kinase activity o f DMPK and protects it from heat-induced inactivation. These results s uggest that MKBP constitutes a novel stress-responsive system independ ent of other known sHSPs in muscle cells and that DMPK may be involved in this system by being activated by MKBP, Importantly, since the amo unt of MKBP protein, but not that of other sHSP family member proteins , is selectively upregulated in skeletal muscle from DM patients, an i nteraction between DMPK and MKBP may be involved in the pathogenesis o f DM.