Calcineurin associates with centrosomes and regulates cilia length maintenance

Abstract

Calcineurin, or PP2B, the Ca2+ and calmodulin-activated phosphatase and target of immunosuppressants, has many substrates and functions that remain undiscovered. By combining rapid proximity-dependent labeling with cell cycle synchronization, we mapped the spatial distribution of calcineurin in different cell cycle stages. While calcineurin-proximal proteins did not vary significantly between interphase and mitosis, calcineurin consistently associated with multiple centrosomal/ciliary proteins. These include POC5, which binds centrin in a Ca2+-dependent manner and is a component of the luminal scaffold that stabilizes centrioles. We show that POC5 contains a calcineurin substrate motif (PxIxIT-type) that mediates calcineurin binding in vivo and in vitro. Using indirect immunofluorescence and ultrastructure expansion microscopy, we demonstrate that calcineurin co-localizes with POC5 at the centriole, and further show that calcineurin inhibitors alter POC5 distribution within the centriole lumen. Our discovery that calcineurin directly associates with centriolar proteins highlights a role for Ca2+ and calcineurin signaling at these organelles. Calcineurin inhibition promotes primary cilia elongation without affecting ciliogenesis. Thus, Ca2+ signaling within cilia includes previously unknown functions for calcineurin in cilia length maintenance, a process frequently disrupted in ciliopathies.

Calcineurin contributes to RNAi-mediated transgene silencing and small interfering RNA production in the human fungal pathogenCryptococcus neoformans

“…A role for calcineurin in RNAi regulation suggests that calcineurin might also be contributing to genome integrity in ways that have not been defined. This is further strengthened by recent studies in humans where calcineurin roles at nuclear pore complexes and centrosomes were discovered (WIGINGTON et al 2020;TSEKITSIDOU et al 2023). In Schizosaccharomyces pombe, RNAi is required for centromere function and if calcineurin has a similar role in regulating RNAi in this fission yeast, it might be directly contributing to genome maintenance and nuclear division (VOLPE et al 2003;FOLCO et al 2008).…”

Calcineurin inhibition, cardiovascular consequences, vascular resistance, and potential responses

“…The amount of IL‐2 being produced by the T‐helper cells significantly influences the extent of the immune response. However, calcineurin has essential roles above and beyond the immune response 5,6 . These functions impact many other bodily systems and remain imperfectly defined.…”

A disease-associated PPP2R3C-MAP3K1 phospho-regulatory module controls centrosome function

“…22 In parallel to these kinases, phosphatases such as calcineurin, Cdc14a, and PP2A (Protein Phosphatase 2A) also control key centrosomal activities. 23–26 PP2A phosphatases represent a series of holoenzyme complexes in which catalytic subunits associate with one of many regulatory subunits that control PP2A activity, localization, and substrate specificity. 27–29 Among PP2A holoenzymes, some localize to centrosomes and regulate centrosome function.…”