Decoding mechanisms and signaling by an s-acylated isoform of calcineurin

The National Institute of General Medical Sciences awarded The Leland Stanford Junior University $152,600 for a Project Grant (CFDA 93.859, Biomedical Research and Research Training) on January 18, 2027, to conduct research decoding mechanisms and signaling by an S-acylated isoform of calcineurin. The award funds a fellowship project investigating how S-acylation and calcium/calmodulin signaling coordinate to regulate CNAB1's membrane localization, catalytic activity, and substrate specificity. The research will identify DHHC enzymes that regulate CNAB1 palmitoylation, determine how S-acylation and calcium/calmodulin co-regulate CNAB1 activity, and define CNAB1-regulated interactomes and signaling pathways using proximity-dependent labeling proteomics. The fellow will gain hands-on experience with high-resolution imaging and mass spectrometry under structured mentorship in scientific writing, communication, and grant preparation, with presentations planned at national conferences including ASBMB. Performance occurs at Palo Alto, California. The period of performance runs through July 19, 2029.

Abstract

The spatial precision of calcium (CA2⁺) signaling at membrane microdomains is vital for orchestrating diverse physiological processes, including neurotransmission, metabolism, and immune responses. Yet how CA2⁺signaling intersects with the reversible lipid modification, s-acylation, to regulate enzyme targeting and activity at membranes remains poorly understood. S-acylation is emerging as a key mechanism for spatial control of signaling that is dysregulated in disease. CNAΒ1, the s-acylated, membrane-anchored isoform of the CA2⁺/calmodulin-regulated phosphatase CN, integrates CA2⁺ and spatial cues to modulate effectors such as the PI4KIIIΑ lipid kinase complex. However, the mechanisms controlling CNAΒ1 localization, activation, and function are not well defined. This fellowship project aims to explain how s-acylation and CA2⁺/calmodulin coordinate to regulate CNAΒ1's membrane localization, catalytic activity, and substrate specificity. The central hypothesis is that specific dhhc acyltransferases mediate CNAΒ1 palmitoylation, enabling CA²⁺-dependent activation and selective engagement of membrane-localized signaling complexes. The proposed research will: (1) identify dhhc enzymes that regulate CNAΒ1 palmitoylation; (2) determine how s-acylation and CA2⁺/calmodulin CO-regulate CNAΒ1 activity; and (3) define CNAΒ1-regulated interactomes and signaling pathways using proximity-dependent labeling proteomics. These studies will uncover principles of lipid- mediated spatial regulation of phosphatase signaling, with implications for diseases linked to disrupted calcium or lipid signaling. To support my training goals, i will gain hands-on experience with high resolution imaging and mass spectrometry, while receiving structured mentorship in scientific writing, communication, and grant preparation. I will present my research at national conferences such as asbmb, while also attending departmental research seminars and events across campus to expand my network and receive feedback on my research. I will participate in career development programs such as "preparing future professors" to enhance my teaching skills. My postdoctoral advisory committee will provide feedback on my research progress and offer guidance as i navigate the job academic market and identify faculty opportunities. The cyert lab is part of several cross- disciplinary communities including BIO-x, chem-h, and the stanford diabetes research center, providing ample opportunities for professional development and scientific communication. Within a collaborative and scientifically rigorous research environment at stanford university, i will receive the mentorship, training, and support needed to advance my research and develop as an independent investigator.