The zinc transporter SLC39A7 (ZIP7) harbours a highly-conserved histidine-rich N-terminal region that potentially contributes to zinc homeostasis in the endoplasmic reticulum

Adulcikas, John; Norouzi, Shaghayegh; Bretag, Lawrence; Sohal, Sukhwinder Singh; Myers, Stephen

doi:10.1016/j.compbiomed.2018.07.007

Cited by 17 publications

(15 citation statements)

References 33 publications

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“…We next sought for the key METTL9 catalyzed residues on SLC39A7. According to the previous studies, SLC39A7 harbors highly-conserved histidine-rich regions that potentially contribute to zinc binding and transport (30,(35)(36)(37). In these histidine-rich regions, we selected two METTL9 motif-containing fragments (residues 203-220 and residues 251-264 of SLC39A7) for further investigation (Fig.…”

Section: Mettl9 Catalyzed Methylhistidine Residues Of Slc39a7 Regulates Cytoplasmic Zinc Homeostasismentioning

confidence: 99%

METTL9 regulates N1-histidine methylation of zinc transporters to promote tumor growth

Cao

Zhang

et al. 2021

Preprint

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Methyltransferase like 9 (Mettl9) is a member of the methyltransferase like protein family which is characterized by the presence of binding domains for S-adenosyl methionine, (SAM), a co-substrate for methylation reactions. Despite METTL9 is predicted to be a methyltransferase, its enzymatic activity, substrate specificities and biological functions are still poorly characterized. In this study, we revealed a tumor-promoting role for METTL9. We found that deletion of Mettl9 in tumor cells suppresses tumor growth and elicits potent anti-tumor immunity. Mechanistically, METTL9 is a N1-histidine methyltransferase which methylates the histidine residues of a x-His-x-His (xHxH) motif on the substrates. This motif is found extensively in zinc transporter families SLC39s and SLC30s, particularly in SLC39A7. Deletion of Mettl9 impairs cytoplasmic zinc homeostasis, resulting in an altered gene expression program with increased endoplasmic reticulum (ER) stress and reduced cell cycle. Mutation of key METTL9 catalyzed methylhistidine residues of SLC39A7 impairs cytoplasmic zinc homeostasis and affects cell growth as well. Notably, METTL9 expression is increased in some cancer types and its higher expression is associated with worse clinical outcomes, particularly in liver and pancreatic cancer. In summary, our work identified METTL9 as a potential new oncogene and its mediated methylation is of regulatory importance. Identifying selective and potent small-molecule inhibitors of METTL9 could thus represent novel therapeutic strategy for anti-proliferative cancer drugs.

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Section: Mettl9 Catalyzed Methylhistidine Residues Of Slc39a7 Regulates Cytoplasmic Zinc Homeostasismentioning

confidence: 99%

METTL9 regulates N1-histidine methylation of zinc transporters to promote tumor growth

Cao

Zhang

et al. 2021

Preprint

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“…Intracellular “free” zinc is sequestered within organelles such as the ER, Golgi and mitochondria with little “free” zinc found within the cytoplasmic [55], thereby, these organelles serve as reservoirs for zinc storage. In this context “free” indicates unbound zinc (in contrast to protein-bound zinc) which depends on the zinc buffering capacity of the cell [15]. While only small concentrations of “free” zinc exist in a cell, it is unquestionably not insignificant.…”

Section: Zincmentioning

confidence: 99%

“…ZIP7 like all SLC39A members, share many conserved regions predominantly within the TMDs and histidine-rich motifs found within the LIV-1 sub-group. The N-terminal region of many LIV-1 members harbours several histidine residues however, ZIP7 has a statistically significantly high proportion of histidine within the N-terminal region relative to the SLC39A family [15]. The function of this high number of histidine residues has not been determined however, the tendency for histidine to be used to bind zinc hints at a yet undiscovered relationship between ER stored zinc and ZIP7.…”

Section: The Zinc Transporter Zip7 In Endoplasmic Reticulum Stressmentioning

confidence: 99%

“…Zinc is stored in the ER and evidence suggests that this metal ion is required for homeostatic functions of this organelle [9]. One zinc transporter that has gained attention in ER-stress and IR-related research is ZIP7 [12,13,14,15,16]. This transporter has been coined the “gate-keeper” of zinc release from the ER into the cytosol and initiates the subsequent zinc-mediated activation of cell signalling pathways that promote cell proliferation and cellular homeostasis [17].…”

Section: Introductionmentioning

confidence: 99%

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Targeting the Zinc Transporter ZIP7 in the Treatment of Insulin Resistance and Type 2 Diabetes

et al. 2019

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Type 2 diabetes mellitus (T2DM) is a disease associated with dysfunctional metabolic processes that lead to abnormally high levels of blood glucose. Preceding the development of T2DM is insulin resistance (IR), a disorder associated with suppressed or delayed responses to insulin. The effects of this response are predominately mediated through aberrant cell signalling processes and compromised glucose uptake into peripheral tissue including adipose, liver and skeletal muscle. Moreover, a major factor considered to be the cause of IR is endoplasmic reticulum (ER) stress. This subcellular organelle plays a pivotal role in protein folding and processes that increase ER stress, leads to maladaptive responses that result in cell death. Recently, zinc and the proteins that transport this metal ion have been implicated in the ER stress response. Specifically, the ER-specific zinc transporter ZIP7, coined the “gate-keeper” of zinc release from the ER into the cytosol, was shown to be essential for maintaining ER homeostasis in intestinal epithelium and myeloid leukaemia cells. Moreover, ZIP7 controls essential cell signalling pathways similar to insulin and activates glucose uptake in skeletal muscle. Accordingly, ZIP7 may be essential for the control of ER localized zinc and mechanisms that disrupt this process may lead to ER-stress and contribute to IR. Accordingly, understanding the mechanisms of ZIP7 action in the context of IR may provide opportunities to develop novel therapeutic options to target this transporter in the treatment of IR and subsequent T2DM.

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“…Zinc is a necessary trace element vital for many proteins to function, and zinc homeostasis requires 24 zinc transporters in humans, 14 of which are ZIPs 42 . Zip7 is a conserved protein found in the ER and Golgi in organisms as diverse as yeast, plants and animals [43][44][45][46][47][48] . In animal cells, loss of ZIP7 can lead to ER stress and in some cases cell death.…”

Section: Introductionmentioning

confidence: 99%

Collective border cell migration requires the zinc transporter Catsup to limit endoplasmic reticulum stress

Guo¹,

Dai

Montell³

2021

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Collective cell migration is critical for normal development, wound healing, and in tumor progression and metastasis. Border cells in the Drosophila ovary provide a genetically tractable model to identify molecular mechanisms that drive this important cell behavior. In an unbiased screen for defects in border cell migration in mosaic clones, we identified a mutation in the catsup gene. Catsup, the Drosophila ortholog of Zip7, is a large, multifunctional, transmembrane protein of the endoplasmic reticulum (ER), which has been reported to negatively regulate catecholamine biosynthesis, to regulate Notch signaling, to function as a zinc transporter, and to limit ER stress. Here we report that catsup knockdown caused ER stress in border cells and that ectopic induction of ER stress was sufficient to block migration. Notch and EGFR trafficking were also disrupted. Wild type Catsup rescued the migration defect but point mutations known to disrupt the zinc ion transport of Zip7 did not. We conclude that migrating cells are particularly susceptible to defects in zinc transport and ER homeostasis.

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The zinc transporter SLC39A7 (ZIP7) harbours a highly-conserved histidine-rich N-terminal region that potentially contributes to zinc homeostasis in the endoplasmic reticulum

Cited by 17 publications

References 33 publications

METTL9 regulates N1-histidine methylation of zinc transporters to promote tumor growth

METTL9 regulates N1-histidine methylation of zinc transporters to promote tumor growth

Targeting the Zinc Transporter ZIP7 in the Treatment of Insulin Resistance and Type 2 Diabetes

Collective border cell migration requires the zinc transporter Catsup to limit endoplasmic reticulum stress

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