Redox Enzymes P4HB and PDIA3 Interact with STIM1 to Fine-Tune Its Calcium Sensitivity and Activation

Du, Yangchun; Wang, Feifan; Liu, Panpan; Zheng, Sisi; Li, Jia; Huang, Rui; Li, Wanjie; Zhang, Xiaoyan; Wang, Youjun

doi:10.3390/ijms25147578

Open AccessArticle

Redox Enzymes P4HB and PDIA3 Interact with STIM1 to Fine-Tune Its Calcium Sensitivity and Activation

by

Yangchun Du

^1,†,

Feifan Wang

^1,†,

Panpan Liu

¹,

Sisi Zheng

¹,

Jia Li

¹,

Rui Huang

¹,

Wanjie Li

¹

,

Xiaoyan Zhang

^1,* and

Youjun Wang

^1,2,*

¹

Beijing Key Laboratory of Gene Resource and Molecular Development, College of Life Sciences, Beijing Normal University, Beijing 100875, China

²

Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, College of Life Sciences, Beijing Normal University, Beijing 100875, China

^*

Authors to whom correspondence should be addressed.

^†

These authors contributed equally to this work.

Int. J. Mol. Sci. 2024, 25(14), 7578; https://doi.org/10.3390/ijms25147578

Submission received: 21 May 2024 / Revised: 7 July 2024 / Accepted: 8 July 2024 / Published: 10 July 2024

(This article belongs to the Section Biochemistry)

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Abstract

Sensing the lowering of endoplasmic reticulum (ER) calcium (Ca²⁺), STIM1 mediates a ubiquitous Ca²⁺ influx process called the store-operated Ca²⁺ entry (SOCE). Dysregulated STIM1 function or abnormal SOCE is strongly associated with autoimmune disorders, atherosclerosis, and various forms of cancers. Therefore, uncovering the molecular intricacies of post-translational modifications, such as oxidation, on STIM1 function is of paramount importance. In a recent proteomic screening, we identified three protein disulfide isomerases (PDIs)—Prolyl 4-hydroxylase subunit beta (P4HB), protein disulfide-isomerase A3 (PDIA3), and thioredoxin domain-containing protein 5 (TXNDC5)—as the ER-luminal interactors of STIM1. Here, we demonstrated that these PDIs dynamically associate with STIM1 and STIM2. The mutation of the two conserved cysteine residues of STIM1 (STIM1-2CA) decreased its Ca²⁺ affinity both in cellulo and in situ. Knockdown of PDIA3 or P4HB increased the Ca²⁺ affinity of wild-type STIM1 while showing no impact on the STIM1-2CA mutant, indicating that PDIA3 and P4HB regulate STIM1’s Ca²⁺ affinity by acting on ER-luminal cysteine residues. This modulation of STIM1’s Ca²⁺ sensitivity was further confirmed by Ca²⁺ imaging experiments, which showed that knockdown of these two PDIs does not affect STIM1-mediated SOCE upon full store depletion but leads to enhanced SOCE amplitudes upon partial store depletion. Thus, P4HB and PDIA3 dynamically modulate STIM1 activation by fine-tuning its Ca²⁺ binding affinity, adjusting the level of activated STIM1 in response to physiological cues. The coordination between STIM1-mediated Ca²⁺ signaling and redox responses reported herein may have implications for cell physiology and pathology.

Keywords: STIM1; STIM2; calcium affinity; P4HB; PDIA3; TXNDC5; SOCE

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MDPI and ACS Style

Du, Y.; Wang, F.; Liu, P.; Zheng, S.; Li, J.; Huang, R.; Li, W.; Zhang, X.; Wang, Y. Redox Enzymes P4HB and PDIA3 Interact with STIM1 to Fine-Tune Its Calcium Sensitivity and Activation. Int. J. Mol. Sci. 2024, 25, 7578. https://doi.org/10.3390/ijms25147578

AMA Style

Du Y, Wang F, Liu P, Zheng S, Li J, Huang R, Li W, Zhang X, Wang Y. Redox Enzymes P4HB and PDIA3 Interact with STIM1 to Fine-Tune Its Calcium Sensitivity and Activation. International Journal of Molecular Sciences. 2024; 25(14):7578. https://doi.org/10.3390/ijms25147578

Chicago/Turabian Style

Du, Yangchun, Feifan Wang, Panpan Liu, Sisi Zheng, Jia Li, Rui Huang, Wanjie Li, Xiaoyan Zhang, and Youjun Wang. 2024. "Redox Enzymes P4HB and PDIA3 Interact with STIM1 to Fine-Tune Its Calcium Sensitivity and Activation" International Journal of Molecular Sciences 25, no. 14: 7578. https://doi.org/10.3390/ijms25147578

APA Style

Du, Y., Wang, F., Liu, P., Zheng, S., Li, J., Huang, R., Li, W., Zhang, X., & Wang, Y. (2024). Redox Enzymes P4HB and PDIA3 Interact with STIM1 to Fine-Tune Its Calcium Sensitivity and Activation. International Journal of Molecular Sciences, 25(14), 7578. https://doi.org/10.3390/ijms25147578

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Redox Enzymes P4HB and PDIA3 Interact with STIM1 to Fine-Tune Its Calcium Sensitivity and Activation

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