A cellular atlas of calcineurin signaling

Ulengin-Talkish, Idil; Cyert, Martha S.

doi:10.1016/j.bbamcr.2022.119366

Cited by 25 publications

(27 citation statements)

References 170 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Dozens of additional essential and non-essential gene products accomplish all these processes. In S. cerevisiae, several proteins involved in vesicular trafficking have been identified as direct substrates of calcineurin (3,64).…”

Section: Discussionmentioning

confidence: 99%

Calcineurin-dependent contributions to fitness in the opportunistic pathogenCandida glabrata

Pavesic,

Gale,

Nickels

et al. 2023

Preprint

View full text Add to dashboard Cite

The protein phosphatase calcineurin is vital for virulence of the opportunistic fungal pathogenCandida glabrata. The host-induced stresses that activate calcineurin signaling are unknown, as are the targets of calcineurin relevant to virulence. To potentially shed light on these processes, millions of transposon insertion mutants throughout the genome ofC. glabratawere profiled en masse for fitness defects in the presence of FK506, a specific inhibitor of calcineurin. 87 specific gene deficiencies depended on calcineurin signaling for full viability in vitro both in wild type andpdr1Δnull strains lacking pleiotropic drug resistance. Three genes involved in cell wall biosynthesis (FKS1, DCW1, FLC1) possess co-essential paralogs whose expression depended on calcineurin and Crz1 in response to micafungin, a clinical antifungal that interferes with cell wall biogenesis. Interestingly, 80% of the FK506-sensitive mutants were deficient in different aspects of vesicular trafficking, such as endocytosis, exocytosis, sorting, and biogenesis of secretory proteins in the ER. In response to the experimental antifungal manogepix that blocks GPI-anchor biosynthesis in the ER, calcineurin signaling increased and strongly prevented cell death independent of Crz1, one of its major targets. Comparisons between manogepix, micafungin, and the ER-stressing tunicamycin reveal a correlation between the degree of calcineurin signaling and the degree of cell survival. These findings suggest that calcineurin plays major roles in mitigating stresses of vesicular trafficking. Such stresses may arise during host infection and in response antifungal therapies.

show abstract

Section: Discussionmentioning

confidence: 99%

Calcineurin-dependent contributions to fitness in the opportunistic pathogenCandida glabrata

Pavesic,

Gale,

Nickels

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…On the other hand, the regulatory sub-unit (CnB) is responsible for binding Ca 2 + and is made of two lobes connected by a linker [ 23 ] . There are three isoforms of CaN: αCaN, βCaN, and γCaN encoded by PPP3CA , PPP3CB , and PPP3CY , respectively [ 24 ] . The αCaN and βCaN isoforms are located in skeletal muscles and other tissues, and the γCaN isoform is located in the brain [ 25 ] .…”

Section: Calcineurin -Structure and Functionsmentioning

confidence: 99%

“…The sarcoplasmic reticulum (ER) plays a crucial role in regulating the replenishment of Ca 2 + stores with the participation of ER Ca 2 + ATPase (SERCA). CaN is also involved in the signaling and regulation of processes occurring in the mitochondria and even participates in protein apoptosis [ 24 ] .…”

Section: Calcineurin -Structure and Functionsmentioning

confidence: 99%

See 1 more Smart Citation

The Ca2+/Calmodulin-dependent Calcineurin/NFAT Signaling Pathway in the Pathogenesis of Insulin Resistance in Skeletal Muscle

Danowska,

Strączkowski

2023

Exp Clin Endocrinol Diabetes

View full text Add to dashboard Cite

Skeletal muscle is the tissue directly involved in insulin-stimulated glucose uptake. Glucose is the primary energy substrate for contracting muscles, and proper metabolism of glucose is essential for health. Contractile activity and the associated Ca2+signaling regulate functional capacity and muscle mass. A high concentration of Ca2+and the presence of calmodulin (CaM) leads to the activation of calcineurin (CaN), a protein with serine-threonine phosphatase activity. The signaling pathway linked with CaN and transcription factors like the nuclear factor of activated T cells (NFAT) is essential for skeletal muscle development and reprogramming of fast-twitch to slow-twitch fibers. CaN activation may promote metabolic adaptations in muscle cells, resulting in better insulin-stimulated glucose transport. The molecular mechanisms underlying the altered insulin response remain unclear. The role of the CaN/NFAT pathway in regulating skeletal muscle hypertrophy is better described than its involvement in the pathogenesis of insulin resistance. Thus, there are opportunities for future research in that field. This review presents the role of CaN/NFAT signaling and suggests the relationship with insulin-resistant muscles.

show abstract

“…Ca 2+ ions direct signaling within subcellular microdomains, where Ca 2+ -dependent effectors colocalize with their substrates ( Ulengin-Talkish and Cyert, 2023 ). One such effector is calcineurin (CN; also known as protein phosphatase 2B, PP2B), a protein phosphatase that is activated by Ca 2+ and calmodulin (CaM), and is inhibited by immunosuppressants, FK506 (also known as tacrolimus) and cyclosporin A (CysA) ( Rusnak and Mertz, 2000 ).…”

Section: Introductionmentioning

confidence: 99%

Calcineurin associates with centrosomes and regulates cilia length maintenance

Tsekitsidou

Wong

Ulengin-Talkish

et al. 2023

Journal of Cell Science

Self Cite

View full text Add to dashboard Cite

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.

show abstract

A cellular atlas of calcineurin signaling

Cited by 25 publications

References 170 publications

Calcineurin-dependent contributions to fitness in the opportunistic pathogenCandida glabrata

Calcineurin-dependent contributions to fitness in the opportunistic pathogenCandida glabrata

The Ca2+/Calmodulin-dependent Calcineurin/NFAT Signaling Pathway in the Pathogenesis of Insulin Resistance in Skeletal Muscle

Calcineurin associates with centrosomes and regulates cilia length maintenance

Contact Info

Product

Resources

About