Modulatory calcineurin-interacting proteins 1 and 2 function as calcineurin facilitatorsin vivo

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Abstract
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 themcip1andmcip2genes in the mouse and provide multiple lines of evidence that endogenous MCIP functions as a calcineurin facilitatorin vivo. Mouse embryonic fibroblasts deficient in bothmcip1/2showed impaired activation of nuclear factor of activated T cells (NFAT), suggesting that MCIP is required for efficient calcineurin–NFAT coupling. Mice deficient inmcip1/2showed a dramatic impairment in cardiac hypertrophy induced by pressure overload, neuroendocrine stimulation, or exercise, similar to mice lackingcalcineurin Aβ. Moreover, simultaneous deletion ofcalcineurin Aβ in themcip1/2-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 inmcip1/2mice, similar tocalcineurin Aβ-null mice. Moreover, CD4+T cells frommcip1/2-null mice showed enhanced apoptosis that was further increased by loss ofcalcineurin Aβ. Finally,mcip1/2-null mice displayed a neurologic phenotype that was similar tocalcineurin 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 signalingin vivo.

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