Specific phosphorylation of αA-crystallin is required for the αA-crystallin-induced protection of astrocytes against staurosporine and C2-ceramide toxicity

We previously reported that alpha A-crystallin and protease-activated receptor are involved in protection of astrocytes against C2-ceramide- and staurosporine-induced cell death (Li et al., 2009). Here, we investigated the molecular mechanism of alpha A-crystallin-mediated cytoprotection. We found that the expression of mutants mimicking specific phosphorylation of alpha A-crystallin increases the protection of astrocytes. However, the expression of mutants mimicking unphosphorylation of alpha A-crystallin results in loss of protection. These data revealed that the phosphorylation of alpha A-crystallin at Ser122 and Ser148 is required for protection. Furthermore, we explored the mechanism of cytoprotection of astrocytes by alpha A-crystallin. Application of specific inhibitors of p38 and ERK abrogates the protection of astrocytes by over-expression of alpha A-crystallin. Thus, p38 and ERK contribute to protective processes by alpha A-crystallin. This is comparable to our previous results which demonstrated that p38 and ERK regulated protease-activated receptor-2 (PAR-2)/alpha B-crystallin-mediated cytoprotection. Furthermore, we found that PAR-2 activation increases the expression of alpha A-crystallin. Thus, endogenous alpha A-crystallin protects astrocytes via mechanisms, which regulate the expression and/or phosphorylation status of alpha A-crystallin. (C) 2012 Elsevier Ltd. All rights reserved.