ISG15 Deregulates Autophagy in Genotoxin-treated Ataxia Telangiectasia Cells

Desai, Shyamal D.; Reed, Ryan E; Babu, Shilka; Lorio, Eric

doi:10.1074/jbc.m112.403832

Cited by 33 publications

(29 citation statements)

References 64 publications

(78 reference statements)

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“…Lysosomal and bacterial staining were performed as previously described [44], [45]. Briefly, RAW cells were treated with 50 nM LysoTracker-Red DND-99 (Life Technology) with and without MMR blocking with 4 mg/ml mannan (Sigma) or 0.5 µg/ml anti-MMR/CD206 pAb (R&D Systems).…”

Section: Methodsmentioning

confidence: 99%

LprG-Mediated Surface Expression of Lipoarabinomannan Is Essential for Virulence of Mycobacterium tuberculosis

et al. 2014

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Mycobacterium tuberculosis employs various virulence strategies to subvert host immune responses in order to persist and cause disease. Interaction of M. tuberculosis with mannose receptor on macrophages via surface-exposed lipoarabinomannan (LAM) is believed to be critical for cell entry, inhibition of phagosome-lysosome fusion, and intracellular survival, but in vivo evidence is lacking. LprG, a cell envelope lipoprotein that is essential for virulence of M. tuberculosis, has been shown to bind to the acyl groups of lipoglycans but the role of LprG in LAM biosynthesis and localization remains unknown. Using an M. tuberculosis lprG mutant, we show that LprG is essential for normal surface expression of LAM and virulence of M. tuberculosis attributed to LAM. The lprG mutant had a normal quantity of LAM in the cell envelope, but its surface was altered and showed reduced expression of surface-exposed LAM. Functionally, the lprG mutant was defective for macrophage entry and inhibition of phagosome-lysosome fusion, was attenuated in macrophages, and was killed in the mouse lung with the onset of adaptive immunity. This study identifies the role of LprG in surface-exposed LAM expression and provides in vivo evidence for the essential role surface LAM plays in M. tuberculosis virulence. Findings have translational implications for therapy and vaccine development.

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Section: Methodsmentioning

confidence: 99%

LprG-Mediated Surface Expression of Lipoarabinomannan Is Essential for Virulence of Mycobacterium tuberculosis

et al. 2014

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“…25 Recently, Desai et al revealed that high ATG7 expression level is associated with poor patient survival in breast cancer. 26 Similar important roles of ATGs have also been demonstrated in the development of other cancers. 27,28 Together, these findings indicate that autophagy plays an important role in carcinogenesis.…”

Section: Introductionmentioning

confidence: 59%

The Thr300Ala variant of ATG16L1 is associated with decreased risk of brain metastasis in patients with non-small cell lung cancer

Xiao

Huang

et al. 2017

Autophagy

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Non-small cell lung cancer (NSCLC) often metastasizes to the brain, but identifying which patients will develop brain metastases (BM) is difficult. Macroautophagy/autophagy is critical for cancer initiation and progression. We hypothesized that genetic variants of autophagy-related genes may affect brain metastases (BM) in NSCLC patients. We genotyped 16 single nucleotide polymorphisms (SNPs) in 7 autophagy-related (ATG) genes (ATG3, ATG5, ATG7, ATG10, ATG12, ATG16L1, and MAP1LC3/LC3) by using DNA from blood samples of 323 NSCLC patients. Further, we evaluated the potential associations of these genes with subsequent BM development. Lung cancer cell lines stably transfected with ATG16L1: rs2241880 (T300A) were established. Mouse models of brain metastasis were developed using cells transfected with ATG16L1-300T or ATG16L1-300A. ATG10: rs10036653 and ATG16L1: rs2241880 were significantly associated with a decreased risk of BM (respective hazard ratios [HRs]D0.596, 95% confidence interval [CI] 0.398-0.894, P D 0.012; and HR D 0. 655, 95% CI 0.438-0.978, P D 0.039, respectively). ATG12: rs26532 was significantly associated with an increased risk of BM (HRD1.644, 95% CI 1.049-2.576, P D 0.030). Invasion and migration assays indicated that transfection with ATG16L1-300T (vs. 300A) stimulated the migration of A549 cells. An in vivo metastasis assay revealed that transfection with ATG16L1-300T (vs. 300A) significantly increased brain metastasis. Our results indicate that genetic variations in autophagy-related genes can predict BM and that genome analysis would facilitate stratification of patients for BM prevention trials.

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“…In addition to blocking polyubiquitin chains formation, protein ISGylation can regulate the UPS system by other means such as competition for E1/E2/E3s ubiquitylation enzymes 50 and for substrate lysines 49 . In combination, these different arms convey a general inhibitory effect on UPS function, which may lead to multiple downstream effects, including the activation of the autophagy pathway 61 , the formation of cellular inclusions 51 , and inflammatory cytokine production (Fan et al . manuscript in preparation).…”

Section: Discussionmentioning

confidence: 99%

Identification and characterization of a novel ISG15-ubiquitin mixed chain and its role in regulating protein homeostasis

Fan

Arimoto

Motamedchaboki

et al. 2015

Sci Rep

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As a ubiquitin-like modifier, ISG15 is conjugated to many cellular proteins in a process termed protein ISGylation. However, the crosstalk between protein ISGylation and the ubiquitin proteasome system is not fully understood. Here, we report that cellular ubiquitin is a substrate of ISG15 and Lys 29 on ubiquitin is the major ISG15 acceptor site. Using a model substrate, we demonstrate that ISG15 can modify ubiquitin, which is immobilized on its substrate, to form ISG15-ubiquitin mixed chains. Furthermore, our results indicate that ISG15-ubiquitin mixed chains do not serve as degradation signals for a ubiquitin fusion degradation substrate. Accordingly, an ISG15-ubiquitin fusion protein, which mimics an ISG15-ubiquitin mixed chain, negatively regulates cellular turnover of ubiquitylated proteins. In addition, ISG15-ubiquitin mixed chains, which are detectable on endogenously ubiquitylated proteins, dampen cellular turnover of these proteins. Thus, our studies unveil an unanticipated interplay between two protein modification systems and highlight its role in coordinating protein homeostasis.

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ISG15 Deregulates Autophagy in Genotoxin-treated Ataxia Telangiectasia Cells

Cited by 33 publications

References 64 publications

LprG-Mediated Surface Expression of Lipoarabinomannan Is Essential for Virulence of Mycobacterium tuberculosis

LprG-Mediated Surface Expression of Lipoarabinomannan Is Essential for Virulence of Mycobacterium tuberculosis

The Thr300Ala variant of ATG16L1 is associated with decreased risk of brain metastasis in patients with non-small cell lung cancer

Identification and characterization of a novel ISG15-ubiquitin mixed chain and its role in regulating protein homeostasis

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