Autophagy, a Novel Pathway to Regulate Calcium Mobilization in T Lymphocytes

Jia, Wei; He, Min; McLeod, Ian X.; He, You–Wen

doi:10.3389/fimmu.2013.00179

Cited by 14 publications

(12 citation statements)

References 79 publications

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“…As we know, the concentration of cytoplasmic free calcium usually remains very low. In response to certain stimuli, the cytoplasmic calcium level can increase sharply by release from the ER or transport from the extracellular environment [ 29 , 43 , 44 ]. Our data showed that triptolide induces ER stress in PCa cells, and the ER stress inhibitors significantly inhibit the accumulation of cytoplasmic calcium and activation of the CaMKKβ-AMPK signaling pathway in the presence of triptolide.…”

Section: Discussionmentioning

confidence: 99%

Triptolide induces protective autophagy through activation of the CaMKKβ-AMPK signaling pathway in prostate cancer cells

et al. 2015

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Triptolide, an active compound extracted from the Chinese herb thunder god vine (Tripterygium wilfordii Hook F.), has potent anti-tumor activity. Recently, triptolide was found to induce autophagy in cancer cells. However, the effects of triptolide on autophagy in human prostate cancer (PCa) cells have not yet been clearly elucidated. In this study, we demonstrated that triptolide induces autophagy in three PCa cell lines, PC-3, LNCaP and C4–2. Furthermore, we found that triptolide mediates intracellular accumulation of free calcium by stimulating the endoplasmic reticulum (ER) stress response. This activates the CaMKKβ-AMPK signaling pathway, which in turn inhibits mTOR and activates both ULK1 and Beclin 1, finally resulting in autophagy. Moreover, we found that treatment with autophagy inhibitors 3-methyladenine (3-MA) and chloroquine (CQ) enhances triptolide-induced PCa cell death and growth inhibition. Using a PC-3-xenografted mouse model, we showed that blocking autophagy with CQ significantly promoted triptolide-induced tumor growth inhibition in vivo. Overall, our results show that triptolide induces protective autophagy through the CaMKKβ-AMPK pathway in PCa cells, implying that a combination of triptolide with autophagy inhibitors may potentially be an effective therapeutic strategy for PCa.

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Section: Discussionmentioning

confidence: 99%

Triptolide induces protective autophagy through activation of the CaMKKβ-AMPK signaling pathway in prostate cancer cells

et al. 2015

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“…However, this is unlikely the reason for the increased amount of ROS that we observed in Atg5-deficient CD8 + T cells because the mitochondrial mass was comparable to that of Atg5-expressing control cells. Besides the mitochondria, the peroxisome and the endoplasmic reticulum could also serve as potential sources of ROS (17,51,52). Additionally, impaired ROS scavenging via the glutathione pathway may also explain why autophagy-deficient CD8 + T cells displayed higher levels of ROS.…”

Section: Discussionmentioning

confidence: 99%

“…Autophagy plays a key role in naive T cell homeostasis and is essential for in vitro T cell activation (15)(16)(17)(18)(19)(20)(21). Bone marrow chimera studies found that deletion of Atg5 resulted in the reduction of peripheral T and B cells (21) whereas Atg5 or Atg7 knockout impaired T cell development due to hyperaccumulation of mitochondria and reactive oxygen species (ROS) (18,22,23).…”

mentioning

confidence: 99%

Survival of Effector CD8+ T Cells during Influenza Infection Is Dependent on Autophagy

Schlie

Westerback

DeVorkin

et al. 2015

The Journal of Immunology

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The activation and expansion of effector CD8+ T cells are essential for controlling viral infections and tumor surveillance. During an immune response, T cells encounter extrinsic and intrinsic factors, including oxidative stress, nutrient availability, and inflammation, that can modulate their capacity to activate, proliferate, and survive. The dependency of T cells on autophagy for in vitro and in vivo activation, expansion, and memory remains unclear. Moreover, the specific signals and mechanisms that activate autophagy in T effector cells and their survival are not known. In this study, we generated a novel inducible autophagy knockout mouse to study T cell effector responses during the course of a virus infection. In response to influenza infection, Atg5−/− CD8+ T cells had a decreased capacity to reach the peak effector response and were unable to maintain cell viability during the effector phase. As a consequence of Atg5 deletion and the impairment in effector-to-memory cell survival, mice fail to mount a memory response following a secondary challenge. We found that Atg5−/− effector CD8+ T cells upregulated p53, a transcriptional state that was concomitant with widespread hypoxia in lymphoid tissues of infected mice. The onset of p53 activation was concurrent with higher levels of reactive oxygen species (ROS) that resulted in ROS-dependent apoptotic cell death, a fate that could be rescued by treating with the ROS scavenger N-acetylcysteine. Collectively, these results demonstrate that effector CD8+ T cells require autophagy to suppress cell death and maintain survival in response to a viral infection.

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“…This might be crucial to provide activated T cells with the necessary degraded intermediates for growth and proliferation. Furthermore, autophagy maintains the ER and therefore regulates calcium mobilization in activated T cells 77 . An mTOR‐independent, glycolysis‐upregulating pathway is also induced upon T‐cell activation and signals via PIM kinases and c‐Jun N‐terminal kinases 78 .…”

Section: Autophagy In Mature T Cellsmentioning

confidence: 99%

Autophagy in T‐cell development, activation and differentiation

2014

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Autophagy is a vital catabolic process for degrading bulky cytosolic contents, which cannot be resorbed via the proteasome. First described as a survival mechanism during nutrient starvation conditions, recent reports have demonstrated that autophagy supports metabolic functions of T cells at various stages of maturation and effector function. Autophagy is crucial for T-cell development at the precursor stage as self-renewability and quiescence of hematopoietic stem cells depend on autophagy of the mitochondria and the endoplasmic reticulum. Later, during development in the thymus, autophagy regulates peptide presentation in stromal cells and professional antigen-presenting cells, which mediate thymocyte selection. Furthermore, the metabolic changes when mature T cells enter the periphery and when they are activated are both dependent on autophagy. Lastly, autophagy prevents early aging and, thus, ensures maintenance of memory T cells. Autophagy is an eukaryotic, cytoplasmic (self-)recycling process, in which proteins as well as entire organelles are degraded via lysosomes. There are three different types of autophagy, namely chaperonemediated autophagy, microautophagy and macroautophagy. Chaperone-mediated autophagy, unlike the other two types of autophagy, only degrades soluble cytosolic proteins by directly transferring heat-shock cognate protein of 70 kDa-tagged proteins across the lysosomal membrane. 1 Both micro-and macroautophagy can be nonselective as well as specific in their cargo selection and both are capable of degrading large-sized molecules. During microautophagy, the lysosomal membrane invaginates to sequester cytosolic content directly. 2 Macroautophagy is distinct, in that a doublemembrane structure, the autophagosome, is formed around its cytosolic cargo. This is also the most well-studied type of autophagy, and as this review deals with macroautophagy, it will be referred to simply as 'autophagy' hereafter.Autophagy is essential for degradation of aggregated proteins (aggrephagy) 3 and damaged organelles including mitochondria (mitophagy), peroxisomes (pexophagy) and ER (ERphagy). These were previously reviewed in Ding and Yin, 4 Sakai et al. 5 and Bernales et al., 6 respectively. As autophagy is a fundamental process needed by almost all cell types to maintain cell homeostasis, a basal level of autophagy occurs constantly. 7 Beyond this, autophagy is vital for cells during stress conditions such as starvation, activation, growth and proliferation, to provide cells with essential metabolic intermediates. These basic autophagic functions are relevant in diseases as well as aging, as the accumulation of aggregated proteins, damaged organelles or other molecules is an underlying problem of many diseases. For instance, autophagy has been implicated in neurodegenerative diseases, 8,9 Crohn's disease, 10,11 cancer, 12,13 aging 4,15 and cystic fibrosis, 16 as well as metabolic-related diseases such as fatty liver (macrolipophagy), 17 autophagic vacuolar myopathies (glycogen degradation) 18,19 and di...

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Autophagy, a Novel Pathway to Regulate Calcium Mobilization in T Lymphocytes

Cited by 14 publications

References 79 publications

Triptolide induces protective autophagy through activation of the CaMKKβ-AMPK signaling pathway in prostate cancer cells

Triptolide induces protective autophagy through activation of the CaMKKβ-AMPK signaling pathway in prostate cancer cells

Survival of Effector CD8+ T Cells during Influenza Infection Is Dependent on Autophagy

Autophagy in T‐cell development, activation and differentiation

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