TRPM7 kinase activity is essential for T cell colonization and alloreactivity in the gut

Romagnani, Andrea; Vettore, Valentina; Rezzonico-Jost, Tanja; Hampe, Sarah; Rottoli, Elsa; Nadolni, Wiebke; Perotti, Michela; Meier, Melanie; Hermanns, Constanze; Geiger, S. E.; Wennemuth, Gunther; Recordati, Camilla; Matsushita, Masayuki; Muehlich, Susanne; Proietti, Michele; Chubanov, Vladimir; Gudermann, Thomas; Grassi, Fabio; Zierler, Susanna

doi:10.1038/s41467-017-01960-z

Cited by 78 publications

(98 citation statements)

References 39 publications

(70 reference statements)

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“…In hepatic and cardiac fibrosis, TRPM7 is upregulated by TGF-β1 stimulation and Smad2/3 phosphorylation 10,36 . In addition, a recent report showed that Smad2 is a substrate of the TRPM7 kinase 3,37 . Thus, TRPM7 upregulation serves as a positive feedback loop to Smad signaling, thereby further aggravating fibrosis 10 .…”

Section: Discussionmentioning

confidence: 99%

TRPM7 contributes to progressive nephropathy

Suzuki

Penner

Fleig

2020

Sci Rep

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TRPM7 belongs to the Transient Receptor Potential Melastatin family of ion channels and is a divalent cation-conducting ion channel fused with a functional kinase. TRPM7 plays a key role in a variety of diseases, including neuronal death in ischemia, cancer, cardiac atrial fibrillation, malaria invasion. TRPM7 is aberrantly over-expressed in lung, liver and heart fibrosis. It is also overexpressed after renal ischemia-reperfusion, an event that induces kidney injury and fibrosis. However, the role of TRPM7 in kidney fibrosis is unclear. Using the unilateral ureteral obstruction (UUO) mouse model, we examined whether TRPM7 contributes to progressive renal damage and fibrosis. We find that TRPM7 expression increases in UUO kidneys. Systemic application of NS8593, a known TRPM7 inhibitor, prevents kidney atrophy in UUO kidneys, retains tubular formation, and reduces TRPM7 expression to normal levels. Cell proliferation of both tubular epithelial cells and interstitial cells is reduced by NS8593 treatment in UUO kidneys, as are TGF-β1/Smad signaling events. We conclude that TRPM7 is upregulated during inflammatory renal damage and propose that pharmacological intervention targeting TRPM7 may prove protective in progressive kidney fibrosis.TRPM7 belongs to the Transient Receptor Potential (TRP) Melastatin family of ion channels, but is unique in that its ion channel domain is fused with a functional serine/threonine kinase 1 . TRPM7 was the first ion channel shown to conduct a range of divalent cations 2,3 , including physiologically essential divalent cations such as Ca 2+ , Mg 2+ , Zn 2+ , Ni 2+ , Mn 2+ , and Co 2+ . Ample evidence supports TRPM7 to be critical in regulating Mg 2+ homeostasis 1 and play a key role in a variety of diseases, including neuronal death in ischemia 4 , renal ischemia 5 , and cardiac atrial fibrillation 6 . TRPM7 is expressed ubiquitously in mammals, and is key in driving cell growth and proliferation, linking the protein to hyperproliferative diseases such cancer 1,7,8 and pulmonary, hepatic, and cardiac fibrosis 6,9-12 . Tissue fibrosis refers to a number of conditions that cause interstitial organ damage followed by inflammation and maladaptive wound healing eventually leading to fibrosis and chronic disease in the organ affected. TRPM7 overexpression leads to fibrosis through the TGF-β signaling pathway 9-11 . Recent in vitro data show that TRPM7 plays a pivotal role in progressive inflammatory and fibrotic disease by promoting excessive extracellular matrix (ECM) deposition 9 . It regulates proliferation and differentiation of fibroblasts 11 and proliferation and polarization of macrophages 13 as well as their Ca 2+ -dependent activation 14 . A recent study supports this hypothesis, as genetic suppression of TRPM7 in a kidney transplantation mouse model alleviated progressive inflammatory kidney fibrosis 15 .In the kidney, cell proliferation is a central response to injury that culminates in the development of fibrosis and renal failure. Unilateral ureteral obstruction (UUO) is a wide...

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Section: Discussionmentioning

confidence: 99%

TRPM7 contributes to progressive nephropathy

Suzuki

Penner

Fleig

2020

Sci Rep

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“…3). Interestingly, the CD103 expression in Trpm7 R/R CD11c + dendritic cells was normal, compared to WT (24). If or how TRPM7 kinase is triggered via TGF- stimulation in T cells is still under investigation.…”

Section: The Channel-kinase Trpm7 In Immune Cell Signallingmentioning

confidence: 99%

“…(26,72,75,80). TRPM7 kinasedeficient mice (Trpm7 R/R ) display altered pro-inflammatory cytokine secretion and lack intra-epithelial T-lymphocytes (IELs) in the gut (24), suggesting a role of TRPM7 kinase activity in gut immune homeostasis. IELs represent a first line of defence within the largest immune organ of our body (84).…”

Section: The Channel-kinase Trpm7 In Immune Cell Signallingmentioning

confidence: 99%

“…A few in vitro TRPM7 kinase substrates have been identified early on, including annexin A1 (20,21), myosin II heavy chain (22) and PLCγ2 (23). Only recently, with the development of novel mouse models, the first native kinase substrate, SMAD2, was discovered, paving the way for more to follow (11,24,25).…”

Section: Introductionmentioning

confidence: 99%

“…It is involved in processes as diverse as proliferation, growth, migration, apoptosis, differentiation and exocytosis (36). Tissue-specific deletion of TRPM7 in thymocytes or macrophages, as well as inactivation of the kinase activity (Trpm7 R/R ) in mice highlights the importance of this unique signalling protein for an operating immune system that is still kept in check (24,26,37). failure, as well as neuroinflammatory diseases (38)(39)(40).…”

Section: Introductionmentioning

confidence: 99%

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The Channel-Kinase TRPM7 as Novel Regulator of Immune System Homeostasis

Nadolni¹,

Zierler²

2018

Preprint

Self Cite

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The enzyme-coupled transient receptor potential channel subfamily M member 7, TRPM7, has been associated with immunity and immune cell signalling. Here, we review the role of this remarkable signalling protein in lymphocyte proliferation, differentiation, activation and survival. We also discuss its role in mast cell, neutrophil and macrophage function and highlight the potential of TRPM7 to regulate immune system homeostasis. Further, we shed light on how the cellular signalling cascades involving TRPM7 channel and/or kinase activity culminate in pathologies as diverse as allergic hypersensitivity, arterial thrombosis, and graft versus host disease (GVHD), stressing the need for TRPM7 specific pharmacological modulators.

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Suppression of transient receptor potential melastatin 7 regulates pluripotency, proliferation, and differentiation of mouse embryonic stem cells via mechanistic target of rapamycin‐extracellular signal‐regulated kinase activation

Kim

Park

Kwon

et al. 2021

J of Cellular Biochemistry

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Mouse embryonic stem cells (mESCs) are a widely used model for their diverse availability in studying early embryonic development and their application in regenerative treatment of various intractable diseases. Transient receptor potential melastatin 7 (Trpm7) regulates Ca2+ as a nonselective ion channel and is essential for early embryonic development; however, the precise role of Trpm7 in mESCs has not been clearly elucidated. In this study, we showed that the inhibition of Trpm7 affects the pluripotency and self‐renewal of mESCs. We found that short hairpin RNA (shRNA)‐mediated suppression of Trpm7 resulted in decreased expression of transcriptional regulators, Oct4 and Sox2, which maintain stemness in mESCs. In addition, Trpm7 knockdown led to alterations in the basic properties of mESCs, such as decreased proliferation, cell cycle arrest at the G0/G1 phase, and increased apoptosis. Furthermore, embryoid body (EB) formation and teratoma formation assays revealed abnormal regulation of differentiation due to Trpm7 knockdown, including the smaller size of EBs, elevated ectodermal differentiation, and diminished endodermal and mesodermal differentiation. We found that EB Day 7 samples displayed decreased intracellular Ca2+ levels compared to those of the scrambled group. Finally, we identified that these alterations induced by Trpm7 knockdown occurred due to decreased phosphorylation of mechanistic target of rapamycin (mTOR) and subsequent activation of extracellular signal‐regulated kinase (ERK) in mESCs. Our findings suggest that Trpm7 could be a novel regulator for maintaining stemness and modulating the differentiation of mESCs.

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TRPM7 kinase activity is essential for T cell colonization and alloreactivity in the gut

Cited by 78 publications

References 39 publications

TRPM7 contributes to progressive nephropathy

TRPM7 contributes to progressive nephropathy

The Channel-Kinase TRPM7 as Novel Regulator of Immune System Homeostasis

Suppression of transient receptor potential melastatin 7 regulates pluripotency, proliferation, and differentiation of mouse embryonic stem cells via mechanistic target of rapamycin‐extracellular signal‐regulated kinase activation

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