Monogenic Lupus

Current Rheumatology Reports, Journal Year: 2016, Volume and Issue: 18(12)

Published: Nov. 3, 2016

Language: Английский

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SAMHD1 is recurrently mutated in T-cell prolymphocytic leukemia

Blood Cancer Journal, Journal Year: 2018, Volume and Issue: 8(1)

Published: Jan. 19, 2018

Abstract T-cell prolymphocytic leukemia (T-PLL) is an aggressive malignancy with a median survival of the patients less than two years. Besides characteristic chromosomal translocations, frequent mutations affect ATM gene, JAK/STAT pathway members, and epigenetic regulators. We here performed targeted mutation analysis for 40 genes selected from RNA sequencing 10 T-PLL in collection 28 T-PLL, exome five further cases. Nonsynonymous were identified 30 genes, 18 being recurrently mutated. mutated previously unknown to be which are SAMHD1 , HERC1 HERC2 PRDM2 PARP10 PTPRC FOXP1 . regulates cellular deoxynucleotide levels acts as potential tumor suppressor other leukemias. observed destructive 18% cases well deletions Taken together, we additional involved signaling ( ), regulation or DNA damage repair PARP10, HERC1, ) T-PLL. Thus, our study considerably extends picture pathways molecular pathogenesis identifies gene ~20% affected by lesions likely major player pathogenesis.

Language: Английский

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TRIM21‐mediated proteasomal degradation of SAMHD1 regulates its antiviral activity

EMBO Reports, Journal Year: 2019, Volume and Issue: 21(1)

Published: Dec. 4, 2019

Abstract SAMHD 1 possesses multiple functions, but whether cellular factors regulate expression or its function remains not well characterized. Here, by investigating why cultured RD and HEK 293T cells show different sensitivity to enterovirus 71 (EV71) infection, we demonstrate that is a restriction factor for EV71. Importantly, identify TRIM 21, an E3 ubiquitin ligase, as key regulator of 1, which specifically interacts degrades through the proteasomal pathway. However, 21 has no effect on EV71 replication itself. Moreover, prove interferon production stimulated infection induces increased expression, whereas increasing overrides inhibition in neonatal mouse model. 21‐mediated degradation also affects 1‐dependent HIV ‐1 regulation production. We further functional domains required binding ubiquitination site K622 phosphorylation at T592 blocks restriction. Our findings illuminate how overcomes via upregulation 21.

Language: Английский

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Tetraspanins interweave EV secretion, endosomal network dynamics and cellular metabolism

European Journal of Cell Biology, Journal Year: 2022, Volume and Issue: 101(3), P. 151229 - 151229

Published: April 27, 2022

Tetraspanin proteins organize membrane nanodomains related to cell adhesion and migration. An essential feature conserved along the superfamily is their cone-shaped tertiary structure, which allows tetraspanins be enriched in highly curved structures. Their conical shape, together with ability associate transmembrane receptors bind cystoskeletal signaling scaffolds, are key regulate endosomal network dynamics Extracellular Vesicle biogenesis cargo selection. Recent evidence suggests that have a relevant impact mitochondria turnover regulation of cellular metabolism. In this review we highlight those reports point as regulators communication between network, EVs

Language: Английский

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De-ubiquitination of SAMHD1 by USP7 promotes DNA damage repair to overcome oncogenic stress and affect chemotherapy sensitivity

Oncogene, Journal Year: 2023, Volume and Issue: 42(22), P. 1843 - 1856

Published: April 20, 2023

Abstract Oncogenic stress induces DNA damage repair (DDR) that permits escape from mitotic catastrophe and allows early precursor lesions during the evolution of cancer. SAMHD1, a dNTPase protecting cells viral infections, has been recently found to participate in process. However, its role tumorigenesis remains largely unknown. Here, we show SAMHD1 is up-regulated early-stage human carcinoma tissues cell lines under oxidative or genotoxic insults. We further demonstrate de-ubiquitinating enzyme USP7 interacts with de-ubiquitinates it at lysine 421, thus stabilizing protein expression for interaction CtIP DDR, which promotes tumor survival stress. Furthermore, levels positively correlates various carcinomas, associated an unfavorable outcome patients who underwent chemotherapy. Moreover, inhibitor sensitizes chemotherapeutic agents by decreasing vitro vivo. These findings suggest de-ubiquitination DDR overcome oncogenic affect chemotherapy sensitivity.

Language: Английский

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Restrictive influence of SAMHD1 on Hepatitis B Virus life cycle

Scientific Reports, Journal Year: 2016, Volume and Issue: 6(1)

Published: May 27, 2016

Abstract Deoxynucleotide triphosphates (dNTPs) are essential for efficient hepatitis B virus (HBV) replication. Here, we investigated the influence of restriction factor SAMHD1, a dNTP hydrolase (dNTPase) and RNase, on HBV We demonstrated that silencing SAMHD1 in hepatic cells increased replication, while overexpression had opposite effect. significantly affected levels extracellular viral DNA as well intracellular reverse transcription products, without affecting RNAs or cccDNA. mutations interfere with dNTPase activity (D137N) catalytic center histidine-aspartate (HD) domain (D311A), phospho-mimetic mutation (T592E), abrogated inhibitory activity. In contrast, diminishing potential RNase but not (Q548A) disabling phosphorylation (T592A) did affect antiviral Moreover, by was rescued addition deoxynucleosides. Although infection directly protein level upregulated dATPs. Interestingly, dephosphorylated, thus potentially antiviral-active state, primary human hepatocytes. Furthermore, type I II interferons cells. These results suggest is relevant restricts through its

Language: Английский

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Interferons Induce Expression of SAMHD1 in Monocytes through Down-regulation of miR-181a and miR-30a

Journal of Biological Chemistry, Journal Year: 2016, Volume and Issue: 292(1), P. 264 - 277

Published: Dec. 2, 2016

Language: Английский

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DNA-Sensing and Nuclease Gene Expressions as Markers for Colorectal Cancer Progression

Oncology, Journal Year: 2016, Volume and Issue: 92(2), P. 115 - 124

Published: Dec. 17, 2016

Oncogene-driven stress-related DNA damage has been observed in lesions of colon cancer. Furthermore, sensors and nucleases are stimulated during active replication. However, their changes influences with respect to cancer remain largely unknown.The gene expression levels cGAS, IFI16, STING, TBK1, IFNB1, TREX1, SAMHD1, RNASEH2A, RNASEH2B, RNASEH2C were examined the paired colorectal adjacent normal part tissues 53 patients. Their associations clinical stages then analyzed.All cytosolic DNA-sensing nuclease-related genes except RNASEH2B showed lower mRNA expressions tumor tissues. Moreover, cGAS upregulation was found be associated early-stage cancers, while higher RNASEH2C, SAMHD1 correlated metastasis. knockdown a cell line impaired migration, analysis RNA-seq data from The Cancer Genome Atlas (TCGA) database revealed negative correlation between E-cadherin levels.In contrast events viral infections or autoimmunity, cGAS-STING-IFNB signaling is disrupted could prognostic markers

Language: Английский

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SAMHD1 Suppression of Antiviral Immune Responses

Trends in Microbiology, Journal Year: 2018, Volume and Issue: 27(3), P. 254 - 267

Published: Oct. 15, 2018

Language: Английский

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Src Tyrosine Kinase Inhibitors: New Perspectives on Their Immune, Antiviral, and Senotherapeutic Potential

Frontiers in Pharmacology, Journal Year: 2019, Volume and Issue: 10

Published: Sept. 18, 2019

Src is the prototypical member of a large family non-receptor protein-tyrosine kinases. Aberrant and altered expression these tyrosine kinases has been extensively reviewed in literature shown to be involved plethora key cellular processes leading tumor development progression. Therefore, have considered an essential target for drug fight malignancies. Since approval, by FDA 2001, first kinase inhibitor (STKI) Imatinib treatment chronic myeloid leukemia (CML), number inhibitors increased notably, Dasatinib being most widely studied. STKIs generally act reducing or stopping aberrant activity several tyrosine-kinase members cells. A decade ago, scientific evidence pointed existence alternative mechanisms involving immune cells microenvironment (cytotoxic T lymphocytes NK). Paradoxically, addition well-known immunosuppressive effect preventing lymphocyte activation, reported increase monoclonal oligoclonal granular lymphocytosis group Dasatinib-treated patients reduced susceptibility opportunistic infections improved prognosis CML receiving drug. Herein we review recent findings on immunomodulatory properties STKIs, including promising role γδ T-lymphocytes, their plausible interest clinic. Moreover, will briefly summarize potential benefits, adverse effects safety concerns regarding viral infections, as well ability alleviate age-associated physical dysfunction impact.

Language: Английский

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