Autophagy enforces functional integrity of regulatory T cells by coupling environmental cues and metabolic homeostasis

Wei, Jun; Long, Ling; Yang, Kai; Guy, Cliff; Shrestha, Sharad; Chen, Zuojia; Wu, Chuan; Vogel, Peter; Neale, Geoffrey; Green, Douglas R.; Chi, Hongbo

doi:10.1038/ni.3365

Cited by 372 publications

(452 citation statements)

References 50 publications

(83 reference statements)

Supporting

Mentioning

416

Contrasting

Unclassified

Order By: Relevance

“…Damage-associated molecular pattern molecules (DAMPS) such as highmobility box group 1 (HMGB1), which are critical regulators of inflammation, also control autophagy levels within tumor cells (Zhu et al 2015). Finally, autophagy was shown to be critical for the development of immunosuppressive T regulatory cells (Wei et al 2016). Taken together, these findings indicate that the role of autophagy in anti-tumor immunity may be highly context-dependent and warrants further study.…”

Section: New Roles For Autophagy Identified In Cancer Progressionmentioning

confidence: 84%

Recent insights into the function of autophagy in cancer

2016

View full text Add to dashboard Cite

Macroautophagy (referred to here as autophagy) is induced by starvation to capture and degrade intracellular proteins and organelles in lysosomes, which recycles intracellular components to sustain metabolism and survival. Autophagy also plays a major homeostatic role in controlling protein and organelle quality and quantity. Dysfunctional autophagy contributes to many diseases. In cancer, autophagy can be neutral, tumor-suppressive, or tumorpromoting in different contexts. Large-scale genomic analysis of human cancers indicates that the loss or mutation of core autophagy genes is uncommon, whereas oncogenic events that activate autophagy and lysosomal biogenesis have been identified. Autophagic flux, however, is difficult to measure in human tumor samples, making functional assessment of autophagy problematic in a clinical setting. Autophagy impacts cellular metabolism, the proteome, and organelle numbers and quality, which alter cell functions in diverse ways. Moreover, autophagy influences the interaction between the tumor and the host by promoting stress adaptation and suppressing activation of innate and adaptive immune responses. Additionally, autophagy can promote a cross-talk between the tumor and the stroma, which can support tumor growth, particularly in a nutrient-limited microenvironment. Thus, the role of autophagy in cancer is determined by nutrient availability, microenvironment stress, and the presence of an immune system. Here we discuss recent developments in the role of autophagy in cancer, in particular how autophagy can promote cancer through suppressing p53 and preventing energy crisis, cell death, senescence, and an anti-tumor immune response.The core autophagy machinery is encoded by autophagyrelated (ATG) genes, of which there are now >30 (Ktistakis and Tooze 2016). These genes and their protein products are regulated by numerous upstream signals, including nutrient availability, stressors, defective organelles, and pathogenic conditions. ATG gene products control the formation of the hallmark double-membrane vesicle, the autophagosome. Other genes encode cargo receptors that direct the cargo to the forming autophagosome. Control of the trafficking machinery then orchestrates fusion of the cargo-laden autophagosomes with lysosomes. Degradative enzymes, contributed by lysosomes, break down the cargo, and the products are exported into the cytoplasm, where they are recycled into metabolic and biosynthetic pathways (Rabinowitz and White 2010;Guo et al. 2016). Under normal nutrient conditions, autophagy functions at a constitutive, low basal level to maintain protein and organelle quality, quantity, and functionality. The ATG genes and autophagy are dramatically induced by starvation and other stressors, which enable cellular and organismal survival. Up-regulation of autophagy is a means to survive nutrient stress, which is conserved from yeast to mammals. More recently, there is a growing appreciation of the role played by ATG genes in modulating intracellular trafficking, endocytosis, exoc...

show abstract

Section: New Roles For Autophagy Identified In Cancer Progressionmentioning

confidence: 84%

Recent insights into the function of autophagy in cancer

2016

View full text Add to dashboard Cite

show abstract

“…52,53 Thymocytes from miR-146b transgenic mice have defective IkB degradation following TCR stimulation and attenuated induction of c-myc. 26,54 As shown in Figure 6A, antagomir treatment increased c-myc expression more than threefold over untreated or scramble-treated tTregs. In addition, consistent with the beneficial effects on viability and expansion, antagomir-treated tTregs had increased expression of antiapoptotic members of the Bcl-2 family (Bcl-xL and Mcl-1) and decreased expression of proapoptotic members (BID and BAX) ( Figure 6B-F).…”

Section: Antagomir-treated Ttregs Show Transcriptional Signs Of Nf-kbmentioning

confidence: 99%

miR-146b antagomir–treated human Tregs acquire increased GVHD inhibitory potency

Hippen

Lemire

et al. 2016

Blood

View full text Add to dashboard Cite

show abstract

“…While in this homeostatic, nonproliferative state, T reg cells switch to FAO-driven OXPHOS as main fuel source and have elevated levels of autophagy [50][51][52]. Two recent studies have shown that autophagy is indeed an essential player in T reg -cell maintenance and function by supporting their metabolic adaption and prevention of excessive glycolysis [51,53]. While the authors note a decrease in the terminal differentiation marker KLRG-1 in T reg cells from Atg16l1 f/f 9 foxp3-Cre mice, they conclude that autophagy deficiency mainly affects T reg -cell maintenance and survival in the context of metabolic adaptation to the intestinal microenvironment.…”

Section: T-cell Development: Autophagy and Energy Metabolismmentioning

confidence: 99%

Mechanistic roles of autophagy in hematopoietic differentiation

Riffelmacher

Simon

2016

The FEBS Journal

View full text Add to dashboard Cite

Autophagy is increasingly recognized for its active role in development and differentiation. In particular, its role in the differentiation of hematopoietic cells has been extensively studied, likely because blood cells are accessible, easy to identify and purify, and their progenitor tree is well defined. This review aims to discuss the mechanisms by which autophagy impacts on differentiation, using hematopoietic cell types as examples. Autophagy's roles include the remodeling during terminal differentiation, the maintenance of a long-lived cell type, and the regulation of the balance between selfrenewal and quiescence in stem-like cells. We discuss and compare the mechanistic roles of autophagy, such as prevention of apoptosis, supply of energy metabolites and metabolic adaption, and selective degradation of organelles and of regulatory factors.

show abstract

Autophagy enforces functional integrity of regulatory T cells by coupling environmental cues and metabolic homeostasis

Cited by 372 publications

References 50 publications

Recent insights into the function of autophagy in cancer

Recent insights into the function of autophagy in cancer

miR-146b antagomir–treated human Tregs acquire increased GVHD inhibitory potency

Mechanistic roles of autophagy in hematopoietic differentiation

Contact Info

Product

Resources

About