The Complex Functions of the NME Family—A Matter of Location and Molecular Activity

Schlattner, Uwe

doi:10.3390/ijms222313083

Cited by 9 publications

(5 citation statements)

References 54 publications

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“…In our previous studies, we chose sponge and human cancer-related homologs with an already determined localization in human cancer cells, namely NME1 [ 70 , 102 , 103 ]) and NME6 [ 104 , 105 , 106 ]. The human NME1 is found in the cytosol and in the nucleus of HeLa cells [ 103 , 106 ], similar to our previous study of its homolog from the marine sponge S. domuncula [ 70 ]. NME6 is a ubiquitously expressed protein localized in the mitochondrial matrix, possibly associated with the mitochondrial inner membrane of human cells [ 104 ].…”

Section: Discussionmentioning

confidence: 99%

Transfection of Sponge Cells and Intracellular Localization of Cancer-Related MYC, RRAS2, and DRG1 Proteins

et al. 2023

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The determination of the protein’s intracellular localization is essential for understanding its biological function. Protein localization studies are mainly performed on primary and secondary vertebrate cell lines for which most protocols have been optimized. In spite of experimental difficulties, studies on invertebrate cells, including basal Metazoa, have greatly advanced. In recent years, the interest in studying human diseases from an evolutionary perspective has significantly increased. Sponges, placed at the base of the animal tree, are simple animals without true tissues and organs but with a complex genome containing many genes whose human homologs have been implicated in human diseases, including cancer. Therefore, sponges are an innovative model for elucidating the fundamental role of the proteins involved in cancer. In this study, we overexpressed human cancer-related proteins and their sponge homologs in human cancer cells, human fibroblasts, and sponge cells. We demonstrated that human and sponge MYC proteins localize in the nucleus, the RRAS2 in the plasma membrane, the membranes of the endolysosomal vesicles, and the DRG1 in the cell’s cytosol. Despite the very low transfection efficiency of sponge cells, we observed an identical localization of human proteins and their sponge homologs, indicating their similar cellular functions.

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Section: Discussionmentioning

confidence: 99%

Transfection of Sponge Cells and Intracellular Localization of Cancer-Related MYC, RRAS2, and DRG1 Proteins

et al. 2023

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“…In addition to providing ATP through oxidative phosphorylation, mitochondria also provide GTP from NME4 and its nucleoside diphosphate kinase activity [8]. This mitochondrial supply of energy is essential for generation of synaptic vesicles for release at axon terminals as well as for vesicular recycling at synapses.…”

Section: Dependence Of Mitochondrial Fission and Fusion On Gtpmentioning

confidence: 99%

“…Major proteins powered by GTP include dynamins for membrane fission and fusion, the small regulatory GTPases, and microtubules as detailed below. Beside de novo synthesis from inosine by IDMPH2 and xanthosine by GMPS, cellular sources of GTP are primarily localized nucleoside diphosphate kinases (NDPKs) from the non-metastatic genes (NME; sometimes called NM23) that convert ATP to GTP [8]. There are at least ten members of the NME gene family but only the first four have nucleoside diphosphate kinase activity.…”

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confidence: 99%

GTP energy dependence of endocytosis and autophagy in the aging brain and Alzheimer’s disease

et al. 2023

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Increased interest in the aging and Alzheimer’s disease (AD)-related impairments in autophagy in the brain raise important questions about regulation and treatment. Since many steps in endocytosis and autophagy depend on GTPases, new measures of cellular GTP levels are needed to evaluate energy regulation in aging and AD. The recent development of ratiometric GTP sensors (GEVALS) and findings that GTP levels are not homogenous inside cells raise new issues of regulation of GTPases by the local availability of GTP. In this review, we highlight the metabolism of GTP in relation to the Rab GTPases involved in formation of early endosomes, late endosomes, and lysosomal transport to execute the autophagic degradation of damaged cargo. Specific GTPases control macroautophagy (mitophagy), microautophagy, and chaperone-mediated autophagy (CMA). By inference, local GTP levels would control autophagy, if not in excess. Additional levels of control are imposed by the redox state of the cell, including thioredoxin involvement. Throughout this review, we emphasize the age-related changes that could contribute to deficits in GTP and AD. We conclude with prospects for boosting GTP levels and reversing age-related oxidative redox shift to restore autophagy. Therefore, GTP levels could regulate the numerous GTPases involved in endocytosis, autophagy, and vesicular trafficking. In aging, metabolic adaptation to a sedentary lifestyle could impair mitochondrial function generating less GTP and redox energy for healthy management of amyloid and tau proteostasis, synaptic function, and inflammation.

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“…We found that NME3 is a selective repressor of ER-phagy. NME3 belongs to a more conserved group of nucleoside diphosphate kinase (NDPK) family, which regulates cellular nucleotide homeostasis and is associated with GTP-dependent cellular processes 121 . However, independent of its NDPK activity, NME3 has been described to regulate mitochondrial dynamics 122 .…”

Section: Discussionmentioning

confidence: 99%

Identification of stress specific autophagy regulators from tandem CRISPR screens

Losier,

Rousseaux,

Russell

2024

Preprint

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Autophagy is a conserved degradative process that promotes cellular homeostasis under stress conditions. Under nutrient starvation autophagy is largely non-selective, promoting the indiscriminate breakdown of cytosolic components. Conversely, selective autophagy is responsible for the specific turnover of damaged organelles including endoplasmic reticula, lysosomes, mitochondria, and peroxisomes. The mechanisms of selective autophagy are best understood through the activity of cargo-specific receptors called autophagy receptors, which facilitate the engulfment of the targeted cargo within autophagosomes, leading to subsequent degradation. We hypothesized that selective autophagy may be regulated by distinct upstream signaling from starvation induced autophagy, providing an additional layer of regulatory control to targeted autophagic degradation. To comprehensively address this question we conducted kinome-wide CRISPR screens to identify distinct signaling pathways responsible for the regulation of basal autophagy, starvation-induced autophagy, and two types of selective autophagy, ER-phagy and pexophagy. These parallel screens identified established and novel autophagy shared regulators under these conditions, as well as kinases specifically required for ER-phagy or pexophagy. More specifically, CDK11A and NME3 were further characterized to be selective ER-phagy regulators. Meanwhile, PAN3 and CDC42BPG were identified as activator or inhibitor of pexophagy, respectively. Collectively, these datasets provide the first comparative description of the kinase signaling specificity, separating regulation of selective autophagy and bulk autophagy.

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The Complex Functions of the NME Family—A Matter of Location and Molecular Activity

Abstract: The family of NME proteins represents a quite complex group of multifunctional enzymes [...]

Cited by 9 publications

References 54 publications

Transfection of Sponge Cells and Intracellular Localization of Cancer-Related MYC, RRAS2, and DRG1 Proteins

Transfection of Sponge Cells and Intracellular Localization of Cancer-Related MYC, RRAS2, and DRG1 Proteins

GTP energy dependence of endocytosis and autophagy in the aging brain and Alzheimer’s disease

Identification of stress specific autophagy regulators from tandem CRISPR screens

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