Calcineurin associates with centrosomes and regulates cilia length maintenance

Tsekitsidou, Eirini; Wang, Jennifer T.; Wong, Cassandra; Ulengin-Talkish, Idil; Stearns, Tim; Gingras, Anne‐Claude; Cyert, Martha S.

doi:10.1101/2022.06.16.496489

Cited by 3 publications

(3 citation statements)

References 70 publications

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“…This is further strengthened by recent studies in humans where calcineurin roles at nuclear pore complexes and centrosomes were discovered (W igington et al . 2020; T sekitsidou et al . 2023).…”

Section: Discussionmentioning

confidence: 99%

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

Yadav¹,

Mohan²,

Sun³

et al. 2023

Preprint

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Adaptation to external environmental challenges at the cellular level requires rapid responses and involves relay of information to the nucleus to drive key gene expression changes through downstream transcription factors. Here, we describe an alternative route of adaptation through a direct role for cellular signaling components in governing gene expression via RNA interference-mediated small RNA production. Calcium-calcineurin signaling is a highly conserved signaling cascade that plays central roles in stress adaptation and virulence of eukaryotic pathogens, including the human fungal pathogenCryptococcus neoformans. Upon activation inC. neoformans, calcineurin localizes to P-bodies, membrane-less organelles that are also the site for RNA processing. Here, we studied the role of calcineurin and its substrates in RNAi-mediated transgene silencing. Our results reveal that calcineurin regulates both the onset and the reversion of transgene silencing. We found that some calcineurin substrates that localize to P-bodies also regulate transgene silencing but in opposing directions. Small RNA sequencing in mutants lacking calcineurin or its targets revealed a role for calcineurin in small RNA production. Interestingly, the impact of calcineurin and its substrates was found to be different in genome-wide analysis, suggesting that calcineurin may regulate small RNA production inC. neoformansthrough additional pathways. Overall, these findings define a mechanism by which signaling machinery induced by external stimuli can directly alter gene expression to accelerate adaptative responses and contribute to genome defense.

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Section: Discussionmentioning

confidence: 99%

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

Yadav¹,

Mohan²,

Sun³

et al. 2023

Preprint

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“…22 In parallel to these kinases, phosphatases such as calcineurin, Cdc14a, and PP2A (Protein Phosphatase 2A) also control key centrosomal activities. [23][24][25][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][28][29] Among PP2A holoenzymes, some localize to centrosomes and regulate centrosome function.…”

Section: Mainmentioning

confidence: 99%

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

Ganga,

Sweeney,

Rubio Ramos

et al. 2024

Preprint

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SummaryCentrosomes have critical roles in microtubule organization and in cell signaling.1–8However, the mechanisms that regulate centrosome function are not fully defined, and thus how defects in centrosomal regulation contribute to disease is incompletely understood. From functional genomic analyses, we find here that PPP2R3C, a PP2A phosphatase subunit, is a distal centriole protein and functional partner of centriolar proteins CEP350 and FOP. We further show that a key function of PPP2R3C is to counteract the kinase activity of MAP3K1. In support of this model,MAP3K1knockout suppresses growth defects caused byPPP2R3Cinactivation, and MAP3K1 and PPP2R3C have opposing effects on basal and microtubule stress-induced JNK signaling. Illustrating the importance of balanced MAP3K1 and PPP2R3C activities, acute overexpression of MAP3K1 severely inhibits centrosome function and triggers rapid centriole disintegration. Additionally, inactivatingPPP2R3Cmutations and activatingMAP3K1mutations both cause congenital syndromes characterized by gonadal dysgenesis.9–15As a syndromicPPP2R3Cvariant is defective in centriolar localization and binding to centriolar protein FOP, we propose that imbalanced activity of this centrosomal kinase-phosphatase pair is the shared cause of these disorders. Thus, our findings reveal a new centrosomal phospho-regulatory module, shed light on disorders of gonadal development, and illustrate the power of systems genetics to identify previously unrecognized gene functions.

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“…However, calcineurin has essential roles above and beyond the immune response. 5,6 These functions impact many other bodily systems and remain imperfectly defined. Insights into calcineurin function, activation, substrate recognition, and targeting have recently been reviewed.…”

mentioning

confidence: 99%

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

Luft

2024

Acta Physiologica

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AimTo place the consequences of calcineurin inhibition in a cardiovascular context.MethodsLiterature review coupled with personal encounters.ResultsCalcineurin is a calcium‐binding and calmodulin‐binding protein that is conserved across evolution from yeast to mammals. The enzyme functions as a calcium‐dependent, calmodulin‐stimulated protein phosphatase. Its role in regulating physiology has largely been elucidated by observing calcineurin inhibition. Calcineurin inhibition transformed organ transplantation from an experiment into a therapy and made much of general immunotherapy possible. The function of this phosphatase and how its inhibition leads to toxicity concern us to this date. Initial research from patients and animal models implicated a panoply of factors contributing to hypertension and vasculopathy. Subsequently, the role of calcineurin in regulating the effective fluid volume, sodium reabsorption, and potassium and hydrogen ion excretion was elucidated by investigating calcineurin inhibition. Understanding the regulatory effects of calcineurin on endothelial and vascular smooth muscle cell function has also made substantial progress. However, precisely how the increase in systemic vascular resistance arises requires further mechanistic research.ConclusionCalcineurin inhibition continues to save lives; however, options to counteract the negative effects of calcineurin inhibition should be vigorously pursued.

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Calcineurin associates with centrosomes and regulates cilia length maintenance

Cited by 3 publications

References 70 publications

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

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

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

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

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