Promotion of vesicular zinc efflux by ZIP13 and its implications for spondylocheiro dysplastic Ehlers–Danlos syndrome

Jeong, Jeeyon; Walker, Joel M.; Wang, Fudi; Park, J. Genevieve; Palmer, Amy E.; Giunta, Cecilia; Rohrbach, Marianne; Steinmann, Beat; Eide, David J.

doi:10.1073/pnas.1211775110

Cited by 101 publications

(95 citation statements)

References 58 publications

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“…We used MLIV fibroblasts to verify these findings and to examine a possible rescue effect of MK6-83 on lysosomal zinc accumulation. We found that LysoTracker positive compartments of TRPML1 À / À fibroblasts displayed strong vesicular FluoZin-3 fluorescence when pretreated with ZnCl 2 as described previously 45,46 . The zinc accumulation in TRPML1 À / À fibroblasts was not reversible on treatment with MK6-83.…”

Section: Mk6-83 Effects On Trafficking and Lysosomal Zinc Buildupmentioning

confidence: 83%

A small molecule restores function to TRPML1 mutant isoforms responsible for mucolipidosis type IV

et al. 2014

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Section: Mk6-83 Effects On Trafficking and Lysosomal Zinc Buildupmentioning

confidence: 83%

A small molecule restores function to TRPML1 mutant isoforms responsible for mucolipidosis type IV

et al. 2014

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“…Zn 2+ also may be redistributed from other intracellular sites into M7Vs. These include mitochondria and NADPH oxidase at the plasma membrane, major sites of ROS that liberate Zn 2+ from the mitochondrial matrix and from metallothioneins (16,17,74). Thus, M7Vs may comprise a sink or reservoir buffering cytosolic Zn 2+ .…”

Section: Discussionmentioning

confidence: 99%

“…Total Zn 2+ increases by 50% during meiotic maturation of oocytes; about half of this increase is released by vesicular exocytosis within minutes of fertilization (69), and the rest persists through preimplantation (70). Because TRPM7 is required for preimplantation development (71), it will be important to determine if the Zn 2+ -containing vesicles in oocytes and early embryos are M7Vs and how changes in GSH/redox during early development (31,72,73) (16,17,74), comparable to the levels required to fill M7Vs in these studies. Zn 2+ also may be redistributed from other intracellular sites into M7Vs.…”

Section: Discussionmentioning

confidence: 99%

TRPM7 senses oxidative stress to release Zn ²⁺ from unique intracellular vesicles

Abiria

Krapivinsky

Sah

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

104

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TRPM7 (transient receptor potential cation channel subfamily M member 7) regulates gene expression and stress-induced cytotoxicity and is required in early embryogenesis through organ development. Here, we show that the majority of TRPM7 is localized in abundant intracellular vesicles. These vesicles (M7Vs) are distinct from endosomes, lysosomes, and other familiar vesicles or organelles. , an ion channel and cytoplasmic kinase, is ubiquitously expressed and essential in early embryonic development (1-4) but also may mediate oxidative stress-induced anoxic neuronal death in adults (5, 6). As an ion channel, TRPM7 conducts Zn 2+ >Mg 2+ ∼ Ca 2+ and monovalent cations (7-10) and contributes to labile cytosolic and nuclear Zn 2+ concentrations (8). TRPM7's C-terminal kinase can phosphorylate multiple substrates (11-13) and is cleaved to release a proapoptotic, chromatin-modifying enzyme (8,14). Zn 2+ regulates TRPM7's kinase activity (11) and binding to transcription factors (8). It is a potent signal for many cellular processes previously related to TRPM7 function, including gene expression, mitosis, and cell survival, but is also proapoptotic at extreme concentrations (15)(16)(17)(18) Oxidative stress increases inward divalent ion permeation through TRPM7 (5, 9), whereas acute and chronic oxidative stress in culture (24-26) or during ischemia-reperfusion in vivo (27, 28) induces TRPM7 expression. The resulting increase in cytosolic Zn 2+ could result in toxic cytosolic concentrations (9). Conversely, reduction of TRPM7 expression protects animals from postischemia reperfusion (5), a condition typically accompanied by increased reactive oxygen species (ROS) and Zn 2+ release from intracellular stores (29). Physiological redox transitions required for stem cell differentiation and gene expression during embryonic development (30, 31) may also be sensed by TRPM7 and transduced via Zn -dependent signals (32). Because TRPM7 patch-clamp recording is limited to the plasma membrane, the assumption has been that TRPM7's main function is on the plasma membrane. However, we have previously shown that TRPM7 is also on intracellular membranes (33-35). Indeed, ROS activation of divalent ion influx through TRPM7 (5, 9) is reminiscent of ROS activation of TRPM2, which releases Ca 2+ and Zn 2+ from lysosomes (36,37 ] and ROS during development and injury.

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“…In addition, ZnT5 −/− / ZnT7 −/− cells displayed an exacerbated ER stress response (26). Similarly, KD of Zip7, Zip13, and ZnT3 in cells induced ER stress and higher cell death, indicating the importance of normal zinc homeostasis for ER stress adaptation (27,28,60).…”

Section: Discussionmentioning

confidence: 99%

“…Zip13 induced or potentiated ER stress (26)(27)(28). The role for ZIP14 in ER stress has not been defined.…”

Section: Significancementioning

confidence: 99%

Hepatic ZIP14-mediated zinc transport is required for adaptation to endoplasmic reticulum stress

Kim

Aydemir

Kim

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Extensive endoplasmic reticulum (ER) stress damages the liver, causing apoptosis and steatosis despite the activation of the unfolded protein response (UPR). Restriction of zinc from cells can induce ER stress, indicating that zinc is essential to maintain normal ER function. However, a role for zinc during hepatic ER stress is largely unknown despite important roles in metabolic disorders, including obesity and nonalcoholic liver disease. We have explored a role for the metal transporter ZIP14 during pharmacologically and high-fat diet-induced ER stress using Zip14 −/− (KO) mice, which exhibit impaired hepatic zinc uptake. Here, we report that ZIP14-mediated hepatic zinc uptake is critical for adaptation to ER stress, preventing sustained apoptosis and steatosis. Impaired hepatic zinc uptake in Zip14 KO mice during ER stress coincides with greater expression of proapoptotic proteins. ER stress-induced Zip14 KO mice show greater levels of hepatic steatosis due to higher expression of genes involved in de novo fatty acid synthesis, which are suppressed in ER stress-induced WT mice. During ER stress, the UPR-activated transcription factors ATF4 and ATF6α transcriptionally up-regulate Zip14 expression. We propose ZIP14 mediates zinc transport into hepatocytes to inhibit protein-tyrosine phosphatase 1B (PTP1B) activity, which acts to suppress apoptosis and steatosis associated with hepatic ER stress. Zip14 KO mice showed greater hepatic PTP1B activity during ER stress. These results show the importance of zinc trafficking and functional ZIP14 transporter activity for adaptation to ER stress associated with chronic metabolic disorders.unfolded protein response | p-eIF2α/ATF4/CHOP pathway | apoptosis | steatosis | zinc metabolism

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Promotion of vesicular zinc efflux by ZIP13 and its implications for spondylocheiro dysplastic Ehlers–Danlos syndrome

Cited by 101 publications

References 58 publications

A small molecule restores function to TRPML1 mutant isoforms responsible for mucolipidosis type IV

A small molecule restores function to TRPML1 mutant isoforms responsible for mucolipidosis type IV

TRPM7 senses oxidative stress to release Zn ²⁺ from unique intracellular vesicles

Hepatic ZIP14-mediated zinc transport is required for adaptation to endoplasmic reticulum stress

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Promotion of vesicular zinc efflux by ZIP13 and its implications for spondylocheiro dysplastic Ehlers–Danlos syndrome

Cited by 101 publications

References 58 publications

A small molecule restores function to TRPML1 mutant isoforms responsible for mucolipidosis type IV

A small molecule restores function to TRPML1 mutant isoforms responsible for mucolipidosis type IV

TRPM7 senses oxidative stress to release Zn 2+ from unique intracellular vesicles

Hepatic ZIP14-mediated zinc transport is required for adaptation to endoplasmic reticulum stress

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Product

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TRPM7 senses oxidative stress to release Zn ²⁺ from unique intracellular vesicles