TMEM33 regulates intracellular calcium homeostasis in renal tubular epithelial cells

Arhatte, Malika; Gunaratne, Gihan S.; Boustany, Charbel El; Kuo, Ivana Y.; Moro, Céline; Duprat, Fabrice; Plaisant, Magali; Duval, Hélène; Li, Dahui; Picard, Nicolas; Couvreux, Anais; Duranton, Christophe; Rubera, Isabelle; Pagnotta, Sophie; Lacas‐Gervais, Sandra; Ehrlich, Barbara E.; Marchant, Jonathan S.; Savage, Aaron M; Eeden, Fredericus J.M. van; Wilkinson, Robert N.; Demolombe, Sophie; Honoré, Eric; Patel, Amanda

doi:10.1038/s41467-019-10045-y

Cited by 18 publications

(14 citation statements)

References 63 publications

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“…The highest scorings proteins associate with IP 3 -receptors in the ER, including: TMEM33 ( p = 4.33E–06; log 2 FC = 20.46), a Ca 2+ regulator affecting acute kidney injury [ 39 , 40 ], ERLINs, which regulate IP 3 receptors, DNAJs regulating degradation, and ARFs controlling G-protein coupled receptors (GPCRs). Consistent with a proposed role in Ca 2+ regulation, we observed MS4A15 localization to the ER (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

MS4A15 drives ferroptosis resistance through calcium-restricted lipid remodeling

et al. 2021

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Ferroptosis is an iron-dependent form of cell death driven by biochemical processes that promote oxidation within the lipid compartment. Calcium (Ca2+) is a signaling molecule in diverse cellular processes such as migration, neurotransmission, and cell death. Here, we uncover a crucial link between ferroptosis and Ca2+ through the identification of the novel tetraspanin MS4A15. MS4A15 localizes to the endoplasmic reticulum, where it blocks ferroptosis by depleting luminal Ca2+ stores and reprogramming membrane phospholipids to ferroptosis-resistant species. Specifically, prolonged Ca2+ depletion inhibits lipid elongation and desaturation, driving lipid droplet dispersion and formation of shorter, more saturated ether lipids that protect phospholipids from ferroptotic reactive species. We further demonstrate that increasing luminal Ca2+ levels can preferentially sensitize refractory cancer cell lines. In summary, MS4A15 regulation of anti-ferroptotic lipid reservoirs provides a key resistance mechanism that is distinct from antioxidant and lipid detoxification pathways. Manipulating Ca2+ homeostasis offers a compelling strategy to balance cellular lipids and cell survival in ferroptosis-associated diseases.

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Section: Resultsmentioning

confidence: 99%

MS4A15 drives ferroptosis resistance through calcium-restricted lipid remodeling

et al. 2021

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“…Interestingly, it was reported that TMEM33, an activator of PKD2, which forms a complex on the endoplasmic reticulum (ER) membrane, but not in primary cilia, fails to regulate PKD2-dependent pronephric renal cystogenesis in zebrafish (Arhatte et al, 2019), indicating that PKD2 located on the ER membrane is not involved in cystogenesis. Thus, the colocalization or interaction of PKD2 and TACAN in the renal primary cilia may be important for TACAN to confer its regulatory role in PKD2 and the associated disease phenotypes in zebrafish.…”

Section: Discussionmentioning

confidence: 99%

Regulation of the PKD2 Channel Function by TACAN

Liu

Zhang

Fatehi

et al. 2021

Preprint

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Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in membrane receptor PKD1 or cation channel PKD2. TACAN (also named TMEM120A), recently reported as an ion channel in neuron cells for mechano and pain sensing, is also distributed in diverse non-neuronal tissues such as kidney, heart and intestine, suggesting its involvement in other functions. In this study, we found that TACAN is in complex with PKD2 in native renal cell lines. Using the two-electrode voltage clamp in Xenopus oocytes we found that TACAN inhibited the channel activity of PKD2 gain-of-function mutant F604P. The first and last transmembrane domains of TACAN were found to interact with the PKD2 C- and N-terminal portions, respectively. We showed that the TACAN N-terminus acted as a blocking peptide and that TACAN inhibits the PKD2 function through the PKD2/TACAN binding. By patch clamping in mammalian cells, we found that TACAN inhibits both the single channel conductance and open probability of PKD2 and mutant F604P. Further, PKD2 co-expressed with TACAN, but not PKD2 alone, exhibited pressure sensitivity. In summary, this study revealed that TACAN acts as a PKD2 inhibitor and mediates mechano sensitivity of the PKD2/TACAN channel complex.

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“…PKD1 could regulate calcium influx via its interaction partner PKD2, which operates as a cation channel that regulates calcium fluxes [2,[5][6][7]. Recently, Arhatte et al reported that PKD2 controls lysosomal calcium loading [56]. It is therefore possible that a lack in Pkd1 perturbs calcium homeostasis in a way that CAPNs are hyperactivated.…”

Section: Discussionmentioning

confidence: 99%

Loss of PKD1/polycystin-1 impairs lysosomal activity in a CAPN (calpain)-dependent manner

et al. 2020

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Mutations in the PKD1 gene result in autosomal dominant polycystic kidney disease (ADPKD), the most common monogenetic cause of end-stage renal disease (ESRD) in humans. Previous reports suggested that PKD1, together with PKD2/polycystin-2, may function as a receptor-cation channel complex at cilia and on intracellular membranes and participate in various signaling pathways to regulate cell survival, proliferation and macroautophagy/autophagy. However, the exact molecular function of PKD1 and PKD2 has remained enigmatic. Here we used Pkd1-deficient mouse inner medullary collecting duct cells (mIMCD3) genetically deleted for Pkd1, and tubular epithelial cells isolated from nephrons of doxycycline-inducible conditional pkd1 fl/fl ;Pax8 rtTA ;TetOCre + knockout mice to show that the lack of Pkd1 caused diminished lysosomal acidification, LAMP degradation and reduced CTSB/cathepsin B processing and activity. This led to an impairment of autophagosomal-lysosomal fusion, a lower delivery of ubiquitinated cargo from multivesicular bodies (MVB)/exosomes to lysosomes and an enhanced secretion of unprocessed CTSB into the extracellular space. The TFEB-dependent lysosomal biogenesis pathway was however unaffected. Pkd1-deficient cells exhibited increased activity of the calcium-dependent CAPN (calpain) proteases, probably due to a higher calcium influx. Consistent with this notion CAPN inhibitors restored lysosomal function, CTSB processing/activity and autophagosomallysosomal fusion, and blocked CTSB secretion and LAMP degradation in pkd1 knockout cells. Our data reveal for the first time a lysosomal function of PKD1 which keeps CAPN activity in check and ensures lysosomal integrity and a correct autophagic flux.

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TMEM33 regulates intracellular calcium homeostasis in renal tubular epithelial cells

Cited by 18 publications

References 63 publications

MS4A15 drives ferroptosis resistance through calcium-restricted lipid remodeling

MS4A15 drives ferroptosis resistance through calcium-restricted lipid remodeling

Regulation of the PKD2 Channel Function by TACAN

Loss of PKD1/polycystin-1 impairs lysosomal activity in a CAPN (calpain)-dependent manner

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