Effects of functionally diverse calpain system on immune cells

Chen, Yueqi; Su, Zhaoliang; Liu, Fang

doi:10.1007/s12026-021-09177-5

Cited by 11 publications

(6 citation statements)

References 111 publications

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“…This protein is an endogenous inhibitor of Calpain [ 41 ], and its phosphorylation state mediated the enzyme activity of Calpain has been reported [ 42 ]. Calpain is a calcium-dependent cysteine protease, and, importantly, it plays a key role in regulating cellular physiological processes, including proteolysis, cytoskeleton remodeling, cell cycle regulation, apoptosis, cell signal transduction, and others [ 43 , 44 ]. Moreover, the biological processes regulated by Calpain was highly related to the results of the above GSEA.…”

Section: Resultsmentioning

confidence: 99%

Fam20c regulates the calpain proteolysis system through phosphorylating Calpasatatin to maintain cell homeostasis

Liu

Zhang

et al. 2023

J Transl Med

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Background The family with sequence similarity 20-member C (FAM20C) kinase, a Golgi casein kinase, which is responsible for phosphorylating the majority of the extracellular phosphoproteins within S-x-E/pS motifs, and is fundamentally associated with multiple biological processes to maintain cell proliferation, biomineralization, migration, adhesion, and phosphate homeostasis. In dissecting how FAM20C regulates downstream molecules and potential mechanisms, however, there are multiple target molecules of FAM20C, particularly many phenomena remain elusive, such as changes in cell-autonomous behaviors, incompatibility in genotypes and phenotypes, and others. Methods Here, assay for transposase-accessible chromatin using sequencing (ATAC-seq), RNA sequencing (RNA-seq), proteomics, and phosphoproteomics were performed in Fam20c-dificient osteoblasts and to facilitate an integrated analysis and determine the impact of chromatin accessibility, genomic expression, protein alterations, signaling pathway, and post translational modifcations. Results By combining ATAC-seq and RNA-seq, we identified TCF4 and Wnt signaling pathway as the key regulators in Fam20c-dificient cells. Further, we showed Calpastatin/Calpain proteolysis system as a novel target axis for FAM20C to regulate cell migration and F-actin cytoskeleton by integrated analysis of proteomics and phosphoproteomics. Furthermore, Calpastatin/Calpain proteolysis system could negatively regulate the Wnt signaling pathway. Conclusion These observations implied that Fam20c knockout osteoblasts would cause cell homeostatic imbalance, involving changes in multiple signaling pathways in the conduction system.

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Section: Resultsmentioning

confidence: 99%

Fam20c regulates the calpain proteolysis system through phosphorylating Calpasatatin to maintain cell homeostasis

Liu

Zhang

et al. 2023

J Transl Med

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“…In line with the prior observation that lysosomal damage‐mediated Ca 2+ release activates calpain and cleaves Atg5 [50], we also observed that TRPM2‐induced Ca 2+ influx decreases the Atg5 expression through calpain. It is noteworthy that calpain has 15 subtypes, which can be classified as conventional and unconventional calpains [62]. Whether all of these calpain subtypes can lead to autophagy inhibition remains to be clarified.…”

Section: Discussionmentioning

confidence: 99%

TRPM2‐dependent autophagy inhibition exacerbates oxidative stress‐induced CXCL16 secretion by keratinocytes in vitiligo

Kang,

Wang,

Chen

et al. 2024

The Journal of Pathology

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Vitiligo is a depigmented skin disease due to the destruction of melanocytes. Under oxidative stress, keratinocyte‐derived chemokine C‐X‐C motif ligand 16 (CXCL16) plays a critical role in recruiting CD8+ T cells, which kill melanocytes. Autophagy serves as a protective cell survival mechanism and impairment of autophagy has been linked to increased secretion of the proinflammatory cytokines. However, the role of autophagy in the secretion of CXCL16 under oxidative stress has not been investigated. Herein, we initially found that autophagy was suppressed in both keratinocytes of vitiligo lesions and keratinocytes exposed to oxidative stress in vitro. Autophagy inhibition also promoted CXCL16 secretion. Furthermore, upregulated transient receptor potential cation channel subfamily M member 2 (TRPM2) functioned as an upstream oxidative stress sensor to inhibit autophagy. Moreover, TRPM2‐mediated Ca2+ influx activated calpain to shear autophagy related 5 (Atg5) and Atg12–Atg5 conjugate formation was blocked to inhibit autophagy under oxidative stress. More importantly, Atg5 downregulation enhanced the binding of interferon regulatory factor 3 (IRF3) to the CXCL16 promoter region by activating Tank‐binding kinase 1 (TBK1), thus promoting CXCL16 secretion. These findings suggested that TRPM2‐restrained autophagy promotes CXCL16 secretion via the Atg5‐TBK1‐IRF3 signaling pathway under oxidative stress. Inhibition of TRPM2 may serve as a potential target for the treatment of vitiligo. © 2024 The Pathological Society of Great Britain and Ireland.

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“…MDL28170 inhibited calpain-2 in the cerebral cortex and downregulated the expression of TNF-α and mature IL-1β, suggesting that calpain-2 is potentially related to inflammation. Chen et al (40) showed that there is a close relationship between calpain and immune cells (especially macrophages, neutrophils and lymphocytes), and that calpain can promote the immune response when immune cells are induced. Therefore, upon the use of MDL28170 after cerebral ischemia, calpain-2 may be blocked at the same time to suppress the immune response of related immune cells, thereby reducing the release of pro-inflammatory cytokines.…”

Section: Discussionmentioning

confidence: 99%

Calpain inhibitor MDL28170 alleviates cerebral ischemia‑reperfusion injury by suppressing inflammation and autophagy in a rat model of cardiac arrest

Wang

Shi²,

Chen³

et al. 2023

Exp Ther Med

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Cerebral ischemia-reperfusion injury (CIRI) is associated with a poor neurological prognosis in patients who have experienced cardiac arrest (CA) and cardiopulmonary resuscitation (CPR). The aim of the current study was to investigate the potential role of a calpain inhibitor in CIRI using a rat model of CA. CA was induced in adult male Sprague-Dawley rats, and MDL28170 (a calpain inhibitor) was administered to the rats within 30 min after the return of spontaneous circulation. Differences between groups were evaluated by measuring survival rate, CPR duration and neurological deficit score. Hematoxylin-eosin staining and Nissl staining were performed to assess cerebral injury, and microstructure and autophagy were assessed by transmission electron microscopy. The levels of calpain-1, calpain-2, calpastatin, interleukin (IL)-1β, tumor necrosis factor (TNF)-α, P62, beclin-1 and LC3 in the brain tissues were determined using western blotting and double immunofluorescence staining. There was no significant difference in CPR duration or survival rate among the groups. At 24 h after CPR, the CA group demonstrated damaged tissue morphology; decreased neurological deficit scores, and P62 expression; and upregulated calpain-2, IL-1βp17, TNF-α, beclin-1 and LC3 levels in the cortex. However, MDL28170 improved neuronal function and suppressed inflammation and autophagy by inhibiting calpain-2 level, but there were no differences in the calpain-1 and calpastatin levels. These results suggest that calpain-2, inflammation and autophagy are involved in CA-induced CIRI. MDL28170 inhibited calpain-2 expression, inflammation and autophagy, which suggests its potential efficacy in treating post-CA nerve damage.

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Effects of functionally diverse calpain system on immune cells

Cited by 11 publications

References 111 publications

Fam20c regulates the calpain proteolysis system through phosphorylating Calpasatatin to maintain cell homeostasis

Fam20c regulates the calpain proteolysis system through phosphorylating Calpasatatin to maintain cell homeostasis

TRPM2‐dependent autophagy inhibition exacerbates oxidative stress‐induced CXCL16 secretion by keratinocytes in vitiligo

Calpain inhibitor MDL28170 alleviates cerebral ischemia‑reperfusion injury by suppressing inflammation and autophagy in a rat model of cardiac arrest

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