Modulatory Calcineurin-Interacting Proteins 1 and 2 Function as Calcineurin Facilitators in vivo

The calcium-activated phosphatase calcineurin is regulated by a binding cofactor known as modulatory calcineurin-interacting protein (MCIP) in yeast up through mammals. The physiologic function of MCIP remains an area of ongoing investigation, because both positive and negative calcineurin regulatory effects have been reported. Here we disrupted the mcipl and mcip2 genes in the mouse and provide multiple lines of evidence that endogenous MCIP functions as a calcineurin facilitator in vivo. Mouse embryonic fibroblasts deficient in both mcipl/2 showed impaired activation of nuclear factor of activated T cells (NFAT), suggesting that MCIP is required for efficient calcineurin-NFAT coupling. Mice deficient in mcipl/2 showed a dramatic impairment in cardiac hypertrophy induced by pressure overload, neuroendocrine stimulation, or exercise, similar to mice lacking calcineurin AP3. Moreover, simultaneous deletion of calcineurin Aβ in the mcip 1/2-null background did not rescue impaired hypertrophic growth after pressure overload. Slow/oxidative fiber-type switching in skeletal muscle after exercise stimulation was also impaired in mcipl/2 mice, similar to calcineurin Aβ-null mice. Moreover, CD4⁺ T cells from mcipl/2-null mice showed enhanced apoptosis that was further increased by loss of calcineurin Aβ. Finally, mcipl/2-null mice displayed a neurologic phenotype that was similar to calcineurin Aβ-null mice, such as increased locomotor activity and impaired working memory. Thus, a loss-of-function analysis suggests that MCIPs serve either a permissive or facilitative function for calcineurin-NFAT signaling in vivo.