Cloning and Analysis of Human Apg16L

Zheng, Huiyong; Ji, Chaoneng; Li, Jixi; Jiang, Hua; Ren, Mengru; Lu, Qiyu; Gu, Shaohua; Mao, Yumin; Xie, Yi

doi:10.1080/10425170400004104

Cited by 24 publications

(15 citation statements)

References 10 publications

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“…Autophagocytosis mediates bulk degradation of cytoplasmic components to the lysosome/vacuole. The process is involved in protein turnover, the starvation response, cellular differentiation, and cell death, but also in the processing of intracellular bacteria (33,34). How this process is implicated in susceptibility for CD remains elusive, although it would support the concept of CD being an inflammatory barrier disorder (35).…”

Section: Discussionmentioning

confidence: 98%

ATG16L1andIL23RAre Associated With Inflammatory Bowel Diseases but Not With Celiac Disease in The Netherlands

Weersma

Zhernakova

Nolte

et al. 2008

The American Journal of Gastroenterology

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Section: Discussionmentioning

confidence: 98%

ATG16L1andIL23RAre Associated With Inflammatory Bowel Diseases but Not With Celiac Disease in The Netherlands

Weersma

Zhernakova

Nolte

et al. 2008

The American Journal of Gastroenterology

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“…49 However, the exact molecular mechanism of ATG16L2 is still unclear. Previously, one study reported that the isoform ATG16L1 was essential for autophagy, while ATG16L2 did not seem to be important.…”

Section: Discussionmentioning

confidence: 99%

Potentially Functional Variants of ATG16L2 Predict Radiation Pneumonitis and Outcomes in Patients with Non–Small Cell Lung Cancer after Definitive Radiotherapy

Jiang

Liu

Wang

et al. 2018

Journal of Thoracic Oncology

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Introduction: Autophagy not only plays an important role in the progression of cancer but also is involved in tissue inflammatory response. However, few published studies have investigated associations between functional genetic variants of autophagy-related genes and radiation pneumonitis (RP) as well as clinical outcomes in patients with non-small cell lung cancer (NSCLC) after definitive radiotherapy. Methods: We genotyped nine potentially functional single nucleotide polymorphisms (SNPs) in four autophagy-related genes (ATG2B, ATG10, ATG12 and ATG16L2) in 393 NSCLC patients of a North American population and assessed their association with RP, local recurrence-free survival (LRFS), progression-free survival (PFS) and overall survival (OS) in multivariate Cox proportional hazards regression analyses. These patients had NSCLC that was treated by definitive radiotherapy. Results: We found that the ATG16L2 rs10898880 CC variant homozygotes had a better LRFS, PFS and OS [adjusted hazards ratio (adjHR) = 0.59, 0.64 and 0.64; 95% confidence interval (95% CI = 0.45-0.79, 0.54-0.96, 0.48-0.84, and 0.48-0.86); and P = 0.0004, 0.002, and 0.003, respectively], but a greater risk of developing severe RP, than patients with CC/CT genotypes (adjHR = 1.80, 96% CI = 1.04-3.12, P = 0.037). Further functional analyses suggested that the ATG16L2 rs10898880 C variant allele modulated gene expression of ATG16L2. Conclusion: This is the first report that functional ATG16L2 C variant homozygous genotype may be a predictor of RP, LRFS, PFS, and OS in NSCLC patients after definitive radiotherapy. Additional larger, prospective studies are needed to confirm these findings.

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“…S1 A and B). The position of the Thr-to-Ala substitution in murine Atg16L1 varies depending on the splice isoform expressed: T300A (isoform β), T281A (isoform α), or T316A (isoform γ) (16). Murine isoform β is the equivalent of human isoform 1, so these mice are hereafter referred to as T300A mice.…”

Section: Resultsmentioning

confidence: 99%

Atg16L1 T300A variant decreases selective autophagy resulting in altered cytokine signaling and decreased antibacterial defense

Lassen

Kuballa

Conway

et al. 2014

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

317

337

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A coding polymorphism (Thr300Ala) in the essential autophagy gene, autophagy related 16-like 1 (ATG16L1), confers increased risk for the development of Crohn disease, although the mechanisms by which single disease-associated polymorphisms contribute to pathogenesis have been difficult to dissect given that environmental factors likely influence disease initiation in these patients. Here we introduce a knock-in mouse model expressing the Atg16L1 T300A variant. Consistent with the human polymorphism, T300A knock-in mice do not develop spontaneous intestinal inflammation, but exhibit morphological defects in Paneth and goblet cells. Selective autophagy is reduced in multiple cell types from T300A knock-in mice compared with WT mice. The T300A polymorphism significantly increases caspase 3-and caspase 7-mediated cleavage of Atg16L1, resulting in lower levels of full-length Atg16Ll T300A protein. Moreover, Atg16L1 T300A is associated with decreased antibacterial autophagy and increased IL-1β production in primary cells and in vivo. Quantitative proteomics for protein interactors of ATG16L1 identified previously unknown nonoverlapping sets of proteins involved in ATG16L1-dependent antibacterial autophagy or IL-1β production. These findings demonstrate how the T300A polymorphism leads to cell typeand pathway-specific disruptions of selective autophagy and suggest a mechanism by which this polymorphism contributes to disease. H uman genetic studies offer an unbiased approach to identify genes and DNA variants underlying susceptibility to complex diseases. Although this approach has been successful at identifying more than 160 loci associated with Crohn disease (CD), a chronic inflammatory condition affecting the gastrointestinal tract (1, 2), ascribing function to specific risk variants has been difficult. Individuals who harbor a common threonine to alanine coding variant at position 300 in autophagy related 16-like 1 (ATG16L1) (T300A) are at increased risk of developing CD compared with individuals who possess a threonine at this position (T300T) (3, 4). The T300A variant lies within a structurally unclassified region of ATG16L1, making it challenging to identify the effect of this polymorphism.ATG16L1 is a component of the core autophagy machinery that plays a critical role in immunity and inflammation. Initial studies investigating ATG16L1 used hypomorphic Atg16L1 mouse models, which show Paneth cell abnormalities relevant to CD such as abnormal mitochondria, irregular patterns of granule morphology and lysozyme distribution, and increased expression of genes implicated in inflammation (5, 6). Although these studies have been useful in highlighting the important role of autophagy proteins in intestinal cells such as Paneth cells and goblet cells, the precise mechanisms by which ATG16L1 T300A influences pathogenesis remain unclear (7)(8)(9)(10).Previous studies have demonstrated that Atg16L1-deficient macrophages produce elevated levels of active caspase 1 and secrete higher levels of the cytokines IL-1β and IL-18 u...

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Cloning and Analysis of Human Apg16L

Cited by 24 publications

References 10 publications

ATG16L1andIL23RAre Associated With Inflammatory Bowel Diseases but Not With Celiac Disease in The Netherlands

ATG16L1andIL23RAre Associated With Inflammatory Bowel Diseases but Not With Celiac Disease in The Netherlands

Potentially Functional Variants of ATG16L2 Predict Radiation Pneumonitis and Outcomes in Patients with Non–Small Cell Lung Cancer after Definitive Radiotherapy

Atg16L1 T300A variant decreases selective autophagy resulting in altered cytokine signaling and decreased antibacterial defense

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