Dynamic S-acylation of the ER-resident protein stromal interaction molecule 1 (STIM1) is required for store-operated Ca2+ entry

Kodakandla, Goutham; West, Savannah J.; Wang, Qiaochu; Tewari, Ritika; Zhu, Michael X.; Akimzhanov, Askar M.; Boehning, Darren

doi:10.1016/j.jbc.2022.102303

Cited by 14 publications

(12 citation statements)

References 35 publications

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“…Our findings were independently confirmed by another group which showed that lack of Orai1 S-acylation also decreased NFATC1 translocation to the nucleus and led to diminished IL-2 production in Jurkat T cells (Carreras-Sureda et al, 2021). Similarly, we found that STIM1 undergoes TCR-dependent S-acylation (Kodakandla et al, 2022). Disruption of the STIM1 S-acylation site (Cys437) did not affect its ER localization, but was critical for the assembly of STIM1 into puncta with Orai1 and proper CRAC channel formation.…”

Section: Orai1/stim1supporting

confidence: 87%

Regulation of T cell function by protein S-acylation

2022

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S-acylation, the reversible lipidation of free cysteine residues with long-chain fatty acids, is a highly dynamic post-translational protein modification that has recently emerged as an important regulator of the T cell function. The reversible nature of S-acylation sets this modification apart from other forms of protein lipidation and allows it to play a unique role in intracellular signal transduction. In recent years, a significant number of T cell proteins, including receptors, enzymes, ion channels, and adaptor proteins, were identified as S-acylated. It has been shown that S-acylation critically contributes to their function by regulating protein localization, stability and protein-protein interactions. Furthermore, it has been demonstrated that zDHHC protein acyltransferases, the family of enzymes mediating this modification, also play a prominent role in T cell activation and differentiation. In this review, we aim to highlight the diversity of proteins undergoing S-acylation in T cells, elucidate the mechanisms by which reversible lipidation can impact protein function, and introduce protein acyltransferases as a novel class of regulatory T cell proteins.

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Section: Orai1/stim1supporting

confidence: 87%

Regulation of T cell function by protein S-acylation

2022

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“…SOCE represents a ubiquitous signaling event observed in both excitable and non-excitable cells, serving as a linchpin in a myriad of physiological and pathophysiological responses 54 . Extensive studies have elucidated the multifaceted regulation of STIM through various post-translational modifications (PTMs), encompassing phosphorylation 55 , acylation 56,57 , glycosylation 18,19 , and oxidation by reactive oxygen species (ROS) 58,59 . Although the N-glycosylation of STIM1 was first reported in 2002 18 there has been a notable lack of further investigations into the potential involvement of deglycosylation enzymes in modulating STIM1 glycosylation over the past two decades.…”

Section: Discussionmentioning

confidence: 99%

Identification of Glucosidase II that regulates STIM1 activation dynamics

Du,

Zheng,

Wang

et al. 2024

Preprint

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The ubiquitous presence of stromal interaction molecule (STIM), endoplasmic reticulum (ER) Ca2+ sensors, plays a crucial role for maintaining Ca2+ homeostasis and signaling in mammalian cells by linking ER Ca2+ depletion with extracellular Ca2+ influx. Although recent advancements have shed light on glycosylation in STIM proteins, further exploration of deglycosylation enzyme modification and its role remains limited by methodological constraints. In this study, leveraging the miniTurbo-driven proximal biotinylation labeling method, we were able to screen for weak and transiently binding protein molecules within specific environments like ER lumina. Herein, we unveil glucosidase II, comprising GANAB and PRKCSH, as a novel partner of the STIM1 complex. Through investigations into Glucosidase II's (Glu II) regulation of STIM1's Ca2+ affinities both in cellulo and in situ, alongside its impact on store-operated Ca2+ entry (SOCE), we propose a novel mechanism wherein Glu II governs STIM1 activation by modulating Ca2+ binding affinity, thereby adjusting the level of activated STIM1 in response to physiological stimulation.

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“…Using Acyl-RAC, STIM1 was shown to be S-acylated on cysteine 437 ( Figure 2 ) in Jurkat T cells and HEK-293 cells. This S-acylation is required for a fully functional SOCE and for efficient STIM1–ORAI1 puncta formation and colocalization [ 62 ], indicating that S-acylation positively regulates STIM1 activation step(s).…”

Section: S-acylation Of Ca 2+ Channels Pumps and E...mentioning

confidence: 99%

S-acylation of Ca2+ transport proteins: molecular basis and functional consequences

Néré,

Kouba,

Carreras-Sureda

et al. 2024

Biochemical Society Transactions

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Calcium (Ca2+) regulates a multitude of cellular processes during fertilization and throughout adult life by acting as an intracellular messenger to control effector functions in excitable and non-excitable cells. Changes in intracellular Ca2+ levels are driven by the co-ordinated action of Ca2+ channels, pumps, and exchangers, and the resulting signals are shaped and decoded by Ca2+-binding proteins to drive rapid and long-term cellular processes ranging from neurotransmission and cardiac contraction to gene transcription and cell death. S-acylation, a lipid post-translational modification, is emerging as a critical regulator of several important Ca2+-handling proteins. S-acylation is a reversible and dynamic process involving the attachment of long-chain fatty acids (most commonly palmitate) to cysteine residues of target proteins by a family of 23 proteins acyltransferases (zDHHC, or PATs). S-acylation modifies the conformation of proteins and their interactions with membrane lipids, thereby impacting intra- and intermolecular interactions, protein stability, and subcellular localization. Disruptions of S-acylation can alter Ca2+ signalling and have been implicated in the development of pathologies such as heart disease, neurodegenerative disorders, and cancer. Here, we review the recent literature on the S-acylation of Ca2+ transport proteins of organelles and of the plasma membrane and highlight the molecular basis and functional consequence of their S-acylation as well as the therapeutic potential of targeting this regulation for diseases caused by alterations in cellular Ca2+ fluxes.

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Dynamic S-acylation of the ER-resident protein stromal interaction molecule 1 (STIM1) is required for store-operated Ca2+ entry

Cited by 14 publications

References 35 publications

Regulation of T cell function by protein S-acylation

Regulation of T cell function by protein S-acylation

Identification of Glucosidase II that regulates STIM1 activation dynamics

S-acylation of Ca2+ transport proteins: molecular basis and functional consequences

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