更新于：2024-09-19

ATG16L1

更新于：2024-09-19

基本信息

别名

APG16-like 1、APG16L、ATG16A

+ [6]

简介

Plays an essential role in both canonical and non-canonical autophagy: interacts with ATG12-ATG5 to mediate the lipidation to ATG8 family proteins (MAP1LC3A, MAP1LC3B, MAP1LC3C, GABARAPL1, GABARAPL2 and GABARAP) (PubMed:23376921, PubMed:23392225, PubMed:29317426, PubMed:30778222, PubMed:33909989, PubMed:24553140, PubMed:24954904, PubMed:27273576). Acts as a molecular hub, coordinating autophagy pathways via distinct domains that support either canonical or non-canonical signaling (PubMed:29317426, PubMed:30778222). During canonical autophagy, interacts with ATG12-ATG5 to mediate the conjugation of phosphatidylethanolamine (PE) to ATG8 proteins, to produce a membrane-bound activated form of ATG8 (PubMed:23376921, PubMed:23392225, PubMed:24553140, PubMed:24954904, PubMed:27273576). Thereby, controls the elongation of the nascent autophagosomal membrane (PubMed:23376921, PubMed:23392225, PubMed:24553140, PubMed:24954904, PubMed:27273576). Also involved in non-canonical autophagy, a parallel pathway involving conjugation of ATG8 proteins to single membranes at endolysosomal compartments, probably by catalyzing conjugation of phosphatidylserine (PS) to ATG8 (PubMed:33909989). Non-canonical autophagy plays a key role in epithelial cells to limit lethal infection by influenza A (IAV) virus (By similarity). Regulates mitochondrial antiviral signaling (MAVS)-dependent type I interferon (IFN-I) production (PubMed:22749352, PubMed:25645662). Negatively regulates NOD1- and NOD2-driven inflammatory cytokine response (PubMed:24238340). Instead, promotes an autophagy-dependent antibacterial pathway together with NOD1 or NOD2 (PubMed:20637199). Plays a role in regulating morphology and function of Paneth cell (PubMed:18849966).

关联

100 项与 ATG16L1 相关的临床结果

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100 项与 ATG16L1 相关的转化医学

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0 项与 ATG16L1 相关的专利（医药）

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项与 ATG16L1 相关的文献（医药）

2106-07-05·Oncotarget

Phospholipid scramblase 1 as a critical node at the crossroad between autophagy and apoptosis in mantle cell lymphoma

Article

作者: Col, Jessica Dal ; Ponzoni, Maurilio ; Faè, Damiana A. ; Dolcetti, Riccardo ; Sigalotti, Luca ; Mastorci, Katy ; Inghirami, Giorgio ; Montico, Barbara

Mantle cell lymphoma (MCL) is an aggressive haematological malignancy in which the response to therapy can be limited by aberrantly activated molecular and cellular pathways, among which autophagy was recently listed. Our study shows that the 9-cis-retinoic acid (RA)/Interferon(IFN)-α combination induces protective autophagy in MCL cell lines and primary cultures reducing the extent of drug-induced apoptosis. The treatment significantly up-regulates phospholipid scramblase 1 (PLSCR1), a protein which bi-directionally flips lipids across membranes. In particular, RA/IFN-α combination concomitantly increases PLSCR1 transcription and controls PLSCR1 protein levels via lysosomal degradation. Herein we describe a new function for PLSCR1 as negative regulator of autophagy. Indeed, PLSCR1 overexpression reduced MCL cell susceptibility to autophagy induced by RA/IFN-α, serum deprivation or mTOR pharmacological inhibition. Moreover, PLSCR1 can bind the ATG12/ATG5 complex preventing ATG16L1 recruitment and its full activation, as indicated by co-immunoprecipitation experiments. The combination of doxorubicin or bortezomib with RA/IFN-α strengthened PLSCR1 up-regulation and enhanced apoptosis, as a likely consequence of the blockade of RA/IFN-α-induced autophagy. Immunohistochemical analysis of 32 MCL biopsies revealed heterogeneous expression of PLSCR1 and suggests its possible implication in the response to anticancer therapies, especially to drugs promoting protective autophagy.

2024-12-01·Molecular Biology Reports

Association of ATG10 rs1864183, ATG16L1 rs2241880 and miR-126 with esophageal cancer

Article

作者: Uppal, Manjit Singh ; Sambyal, Vasudha ; Bali, Jagmohan Singh ; Gupta, Priyanka ; Mehrotra, Sanjana ; Sudan, Meena ; Guleria, Kamlesh

BACKGROUNDIn India, esophageal cancer (EC) is among the major cause of cancer-related deaths in both sexes. In recent past, autophagy has emerged as one of the crucial process associated with cancer. In the development of EC, the role of autophagy and the precise molecular mechanism involved has yet to be fully understood. Recently, a small number of studies have proposed how variations in autophagy genes affect the growth and development of EC. Micro-RNA's are also known to play a critical role in the development of EC. Here, we examined the relationship between the risk of EC and two single-nucleotide polymorphisms (SNPs) in the key autophagy genes, ATG10 rs1864183 and ATG16L1 rs2241880. We also analyzed the association of miR-107 and miR-126 with EC as these miRNA's are associated with autophagy.METHODS AND RESULTSA total of 230 EC patients and 230 healthy controls from North-west Indian population were enrolled. ATG10 rs1864183 and ATG16L1 rs2241880 polymorphism were analyzed using TaqMan genotyping assay. Expression levels of miR-107 and miR-126 were analyzed through quantitative PCR using SYBR green chemistry. We found significant association of CT + CC genotype (OR 0.64, p = 0.022) in recessive model for ATG10 rs1864183 polymorphism with decreased EC risk. For ATG16L1 rs2241880 polymorphism significant association for AG genotype (OR 1.48, p = 0.05) and G allele (OR 1.43, p = 0.025) was observed for increased EC risk. Expression levels of miR-126 were also found to be significantly up regulated (p = 0.008).CONCLUSIONOur results suggest that ATG10 rs1864183, ATG16L1 rs2241880 and miR-126 may be associated with esophageal carcinogenesis and warrant further investigation.

2024-11-01·European Journal of Pharmaceutical Sciences

Genetic polymorphisms and their association with methotrexate polyglutamates during maintenance treatment in Korean children and young adults with acute lymphoblastic leukemia

Article

作者: Choi, Rihwa ; Ju, Hee Young ; Kim, Min-Ji ; Lee, Ji Won ; Lee, Soo-Youn

The aim of this study was to investigate the impact of genetic polymorphisms on methotrexate (MTX) metabolism in Korean children and young adults with acute lymphoblastic leukemia, specifically focusing on MTX polyglutamates (MTX-PGs) in erythrocytes, which have been rarely studied. Korean children and young adult patients undergoing maintenance therapy for acute lymphoblastic leukemia, who were receiving weekly oral MTX doses of 20 mg/m²/week, were prospectively included. We investigated erythrocyte MTX-PG (PG1 to PG5) levels, MTX-PG/MTX dose ratios, and 222 genetic polymorphisms spanning 78 genes and three intergenic areas related to MTX transport, folate cycle metabolism, purine/pyrimidine pathways, and non-pathway genes (including TPMT and NUDT15 genotypes) to explore their association with MTX metabolism. MTX-PG levels were associated with MTX dose (p < 0.05), and MTX-PG3 comprised the majority of the total MTX-PGs, with a median of 39.3%. Various polymorphisms within the same gene demonstrated differing associations with each type of MTX-PG, underscoring the complexity of MTX pharmacogenetics. Among the polymorphisms examined, 14 across 13 genes showed significant associations with MTX-PG2-5 levels, even after adjusting for the false discovery rate (ABCC5, ATG16L1, CEP72, FSTL5, GMPS, HTR3A, IMPDH1, NT5C2, SLC28A3, SLCO1B3, SUCLA2, TPMT, and TYMS). This study enhances our understanding of genetic polymorphisms in MTX metabolism and therapeutic monitoring for MTX maintenance, promoting personalized medicine in acute lymphoblastic leukemia patients.

项与 ATG16L1 相关的新闻（医药）

2022-09-26

·生物制药小编

RIPK1介导自免和神经退行性疾病

2022年8月2日维泰瑞隆完成了2亿美金B轮融资，基于RIPK1的多款产品是其目前进展最快的管线。维泰瑞隆官网在此之前，5月2日，德纳利(DNLI）与赛诺菲(Sanofi）合作开发的用于治疗肌萎缩侧索硬化症（ALS）的SAR443820（DNL788）开始了Ⅱ期临床研究。SAR443820 是RIPK1的中枢神经系统 (CNS) 渗透性小分子抑制剂。RIPK1是炎症和死亡信号传递的重要介质，是神经退行性疾病、自身免疫性疾病和炎症等多种疾病治疗的有效靶点之一。RIPK1简介RIPK1是人类疾病中对刺激做出反应的调节因子，它能够在细胞生存与死亡之间做出决定，参与调控细胞炎症、凋亡、坏死过程。通路：在TNFα的刺激下，RIPK1与TRADD、TNFR1死亡结构域结合，迅速被招募到复合体1（Complex 1）中，通过泛素化、磷酸化等一系列PTM，激活下游NF-κB的生存或者死亡信号。RIPK1蛋白结构分为三个部分：C端死亡域：介导与其他含有死亡结构域的蛋白质，如FADD，TNFR1和Fas的同源二聚和异源二聚。N端激酶域：末端激酶结构域介导反式蛋白的自磷酸化以促进其自身的激活。中间域：包含RIP同型相互作用基序（RHIM）。功能：RIPK1具有双向作用：一方面，RIPK1作为结构支架，能够促进NF-κB通路激活，促进细胞生存、抑制凋亡；而另一方面作为激酶，可以促进细胞死亡和炎症。相关疾病RIPK1及其调控基因突变会导致多种疾病，包括自身免疫疾病、自体炎症、神经退行性疾病等。以下基因直接参与调控RIPK1活性，在自身免疫和自体炎症中发生突变。TNFAIP3：编码A20，通过调节RIPK1、TRFF6、NEMO等关键信号的泛素化，限制TLR和TNF诱导的炎症反应。IKBKG：编码的NEMO是IKKα、IKKβ组成的支架亚单位，在NF-κB通路的激活中起关键作用。TNIP1：编码的ABIN1与线性泛素链结合，与A20相互作用，通过NF-κB通路调节先天免疫反应。TNIP1突变会造成炎症反应，通过抑制RIPK1能够减轻炎症反应而不影响宿主正常免疫功能。OTULIN：是一种M1泛素链的去泛素化酶，OTULIN突变患者会有强烈的炎症特性，最终会激活细胞程序性坏死。LUBAC复合体：由HOIP、HOIL1、Sharpin组成，LOF和HOIP、HOIL1亚型突变会出现免疫缺陷和自身免疫炎症性疾病。基因突变造成的疾病：IBD：炎症性肠病A20表达升高和减少都与IBD相关，同时ATG16L1也是IBD危险因素。银屑病：银屑病中TNFAIP3和A20蛋白水平的降低可能与疾病严重程度降低相关，同时也可作为预测TNF治疗疗效临床标志物。RA：类风湿关节炎患者TNFAIP3表达降低。MS：多发性硬化症TNFAIP3高表达。SLE：系统性红斑狼疮存在TNFAIP3和TNIP1的多个独立的核苷酸多态性。介于RIPK1在细胞凋亡中的作用，神经退行性疾病也与RIPK1高度相关：ALS：脊髓侧索硬化症FTD：额颞叶痴呆存在OPTN、TBK1两个基因LOF (loss-of-function) 突变。OPTN缺失或功能减弱，导致RIPK1降解减少；TBK1单倍剂量不足，导致RIPK1过度激活。AD：阿尔兹海默病观察到RIPK1/RIPK3-MLKL激活增加，可能引起AD中的神经炎。RIPK1可能控制多种神经退行性疾病和衰老相关的神经炎性通路。PD：帕金森LRRK2表达上调，通过RIPK1依赖机制导致细胞凋亡。多种疾病都与RIPK1激酶属性的异常激活相关，因此RIPK1抑制剂就成为人类疾病治疗中的开发靶点。药物研发进展RIPK1抑制剂已进入人体临床试验，用于神经退行性疾病、自身免疫病、溃疡性结肠炎、类风湿等疾病治疗。相比TNFα抑制剂，RIPK1在CNS中的安全性高、参与更广泛的促炎症活性、各药物研发时间表GSK'772是第一个进入Ⅰa期临床研究的RIPK1激酶抑制剂，在溃疡性结肠炎、类风湿关节炎、银屑病的Ⅱ期临床完成后，目前正在进行更高剂量的银屑病临床试验。DNL104是第一款能够透过血脑屏障的RIPK1抑制剂，试验中展示出在CNS中抑制RIPK1具有很高的安全性。随后DNLI公司进行了DNL747、DNL758、DNL788开发。小结RIPK1抑制剂在患者身上的临床试验仍处于早期阶段，开发选择性、高效和安全的RIPK1小分子抑制剂，并可靠地衡量RIPK1激酶抑制的临床疗效和患者分层仍然是未来临床发展面临的关键挑战。参考资料https://www.globenewswire.com/news-release/2022/05/02/2433539/0/en/Denali-Therapeutics-Announces-Achievement-of-RIPK1-Milestone-for-Phase-2-Clinical-Trial-Initiation-in-ALS-by-Sanofi.htmlYuan J et al. Necroptosis and RIPK1-mediated neuroinflammation in CNS diseases. Nat Rev Neurosci. 2019 Jan;20(1):19-33. Zhang X et al. RIPK1 can mediate apoptosis in addition to necroptosis during embryonic development. Cell Death Dis. 2019 Mar 13;10(3):245. https://denalitherapeutics.com/investors/press-release?id=626

小分子药物免疫疗法合作

2022-08-31

·生物谷

抗衰老神药来了？Nature子刊：青壮年时短期服用雷帕霉素，可获得终身抗衰老效果

近年来，随着全球老龄化的加速，世界各国纷纷掀起了一股抗衰老研究的热潮，各种抗衰老药物和疗法也相继被发掘。近日马克斯普朗克衰老生物学研究所的研究人员，在《自然-衰老》刊登出他们有关雷帕霉素最新研究成果：Long-lasting geroprotection from brief rapamycin treatment in early adulthood by persistently increased intestinal autophagy。该项研究发现果蝇与小鼠在成年前期服用雷帕霉素，与终身长期服用的延寿抗衰效果相同，对于寿命的延长效果相似。研究人员首先对果蝇服用雷帕霉素最佳时间段开展考察，结果发现在成年开始的第1~30天时间段服用时（以交配完成的当天作为成年第1天，以下简称短期组），果蝇的寿命延长效果均高于其他时间段，而且与终身长期服用（从交配完成到死亡为止，以下简称长期组）的寿命延长效果相当。图1. 雷帕霉素不同给药时间段对于果蝇寿命的影响果蝇短期组雷帕霉素的摄入时间段约为长期组的1/3，但是二者效果却相当，这是为何呢？研究人员开始初步在机制层面深入探究，结果发现短期组在前期30天摄入雷帕霉素可以起到长期降低TORC1（其表达被抑制，代表着抗衰作用增强）活性的作用。在第30天，两组果蝇的大脑、肌肉、脂肪组织、肠道TORC1表达水平相同，均显著低于对照组。TORC1表达降低的原因在于短期组摄入雷帕霉素使得肠道细胞自噬增加，长期组观察到溶酶体增加，而不增加自噬小体，引发自噬流。图2. 雷帕霉素成年初期短暂摄入与长期摄入在提升果蝇寿命、保护肠道健康上的影响已有研究表明Atg1过度表达会导致果蝇自噬发生，在本研究中短期组在停止给药后的1～15天，肠道上皮细胞Atg1均过度表达，持续性下调了 Ref-2-P 。Atg1过度表达延长了果蝇寿命，同时减少了因为衰老导致的肠道完整性损伤。图3. 短期Atg1过度表达可诱导果蝇持久自噬激活、延寿接着为了探明是否因为组蛋白表达增加，而使得雷帕霉素能够延长寿命。研究人员分别对短期组、长期组的组蛋白H3 表达分析，结果表明长期组内组蛋白H3是增加状态，但是在短期组停止摄入15天后就恢复到对照组水平，说明组蛋白表达的增加并不是短期组延寿的原因。图4. 短期摄入雷帕霉素对自噬、延寿、肠道屏障功能的影响为了查明短期增寿原因，找到雷帕霉素的调控者，研究人员开展了蛋白组学分析。蛋白质组学结果：与短链脂肪酸代谢、碳水化合物代谢、溶酶体α-甘露糖苷酶相关的蛋白含量上调。使用RT–qPCR技术开展差异物质筛选，结果得知溶酶体-甘露糖苷酶（LmanV）的mRNA表达水平显著上调。上述筛选结果使得研究人员思考：LmanV是否才是雷帕霉素短期作用的关键，因为该酶与溶菌酶共同作用，推动细胞自噬，延缓肠道老化。研究人员紧接着使用RNAi技术沉默该基因表达，结果短期组的延寿效果，肠道衰老改善等都不再出现。当在无雷帕霉素摄入果蝇成年前期，过度表达该基因时，果蝇肠道老化病理表现减少，LmanV含量与长期组相同。以上结果说明，雷帕霉素短期作用的关键的确是LmanV，通过LmanV引发自噬、改善肠道健康。最近多篇研究表明哺乳动物小肠溶酶体分泌产生自噬作用，也是维护肠道健康重要手段。分泌自噬在应对感染时会激活产生自噬蛋白Atg5、Atg16L1。研究人员也关注到了这一点，探究分泌自噬作用是否也参与到改善衰老过程，结果得知短期组与长期组的溶酶体水平均高于对照组。短期组在服用雷帕霉素时，使LmanV、Atg5沉默表达会降低果蝇肠道溶酶体水平。由此研究人员得知，雷帕霉素通过肠道分泌自噬与LmanV进一步上调了溶酶体水平。图5. 短期雷帕霉素摄入持续增加LmanV、减少肠道衰老为了验证雷帕霉素在哺乳动物短期作用也与长期作用相当，研究人员接着在小鼠上开展探究。选择三批小鼠，分别为对照组、短期组、长期组，短期组在小鼠3~6月（相当于人的青壮年时期）摄入雷帕霉素，长期组则是持续到12月。结果得到与对照组相比，短期组与长期组均能显著降低LBP含量，且二者之间无显著性差异。对回肠绒毛紧密连接蛋白（TJs）超微结构与含量的检测，结果：对照组内TJs含量降低、完整性随着衰老而破坏，电子密度降低，肠道的通透性增加，而短期组与长期组则有着显著改善，且两组之间无显著性差异。此结果证明雷帕霉素的短期摄入能够对肠道完整性产生终身积极影响。图6. 短期雷帕霉素摄入维持肠道屏障功能和Paneth细胞结构稳定此外，短期组中的雷帕霉素改善了衰老相关的潘氏细胞形态学问题、提升了肠道屏障功能，短期组与长期组改善效果相似，无显著差异。综上所述，雷帕霉素在雌性果蝇成年之后连续服用30天可以显著延长寿命，在小鼠3~6月时间段补充雷帕霉素同样能够显著延长寿命。雷帕霉素在延寿的同时还能改善相关的衰老问题，而且短期摄入的改善效果与终身摄入相同。果蝇上延寿的机制为肠细胞自噬作用增强，伴随肠道LManV和溶菌酶水平升高。在小鼠中，雷帕霉素作用机制在于改善TJs含量与完整性、肠道通透性、Paneth细胞结构和肠道屏障功能。图7. 短期雷帕霉素摄入增加了Paneth细胞中溶菌酶和p62阳性颗粒本项研究的意义在于为将来研究雷帕霉素对于其他器官系统的衰老，如心血管、免疫、认知功能等做基础，而且对这些课题深入研究将减少雷帕霉素在临床上使用的副作用、丰富衰老理论。参考文献：1.Juricic, P., Lu, YX., Leech, T. et al. Long-lasting geroprotection from brief rapamycin treatment in early adulthood by persistently increased intestinal autophagy. Nat Aging (2022). https://doi.org/10.1038/s43587-022-00278-w2.Turco E, Fracchiolla D, Martens S. Recruitment and Activation of the ULK1/Atg1 Kinase Complex in Selective Autophagy. J Mol Biol. 2020 Jan 3;432(1):123-134. doi: 10.1016/j.jmb.2019.07.027. Epub 2019 Jul 25. PMID: 31351898; PMCID: PMC6971721.3.Filali-Mouncef Y, Hunter C, Roccio F, Zagkou S, Dupont N, Primard C, Proikas-Cezanne T, Reggiori F. The ménage à trois of autophagy, lipid droplets and liver disease. Autophagy. 2022 Jan;18(1):50-72. doi: 10.1080/15548627.2021.1895658. Epub 2021 Apr 2. PMID: 33794741; PMCID: PMC8865253.4.Onorati AV, Dyczynski M, Ojha R, Amaravadi RK. Targeting autophagy in cancer. Cancer. 2018 Aug;124(16):3307-3318. doi: 10.1002/cncr.31335. Epub 2018 Apr 19. PMID: 29671878; PMCID: PMC6108917.5.Levine B, Kroemer G. Biological Functions of Autophagy Genes: A Disease Perspective. Cell. 2019 Jan 10;176(1-2):11-42. doi: 10.1016/j.cell.2018.09.048. PMID: 30633901; PMCID: PMC6347410.6.Bel S, Hooper LV. Secretory autophagy of lysozyme in Paneth cells. Autophagy. 2018;14(4):719-721. doi: 10.1080/15548627.2018.1430462. Epub 2018 Mar 8. PMID: 29388875; PMCID: PMC5959324.7.Lu R, Zhang YG, Xia Y, Sun J. Imbalance of autophagy and apoptosis in intestinal epithelium lacking the vitamin D receptor. FASEB J. 2019 Nov;33(11):11845-11856. doi: 10.1096/fj.201900727R. Epub 2019 Jul 30. PMID: 31361973; PMCID: PMC6902693.撰文｜毛桃编辑｜小耳朵