Class I PI3K Provide Lipid Substrate in T Cell Autophagy Through Linked Activity of Inositol Phosphatases.

Ian X. McLeod,Ruchi Saxena,You-Wen He,Zachary Carico

doi:10.3389/fcell.2021.709398

Ian X. McLeod, Ruchi Saxena + Show 2 more

Open Access

https://doi.org/10.3389/fcell.2021.709398

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Abstract

Autophagy, a highly conserved intracellular process, has been identified as a novel mechanism regulating T lymphocyte homeostasis. Herein, we demonstrate that both starvation- and T cell receptor-mediated autophagy induction requires class I phosphatidylinositol-3 kinases to produce PI(3)P. In contrast, common gamma chain cytokines are suppressors of autophagy despite their ability to activate the PI3K pathway. T cells lacking the PI3KI regulatory subunits, p85 and p55, were almost completely unable to activate TCR-mediated autophagy and had concurrent defects in PI(3)P production. Additionally, T lymphocytes upregulate polyinositol phosphatases in response to autophagic stimuli, and the activity of the inositol phosphatases Inpp4 and SHIP are required for TCR-mediated autophagy induction. Addition of exogenous PI(3,4)P2 can supplement cellular PI(3)P and accelerate the outcome of activation-induced autophagy. TCR-mediated autophagy also requires internalization of the TCR complex, suggesting that this kinase/phosphatase activity is localized in internalized vesicles. Finally, HIV-induced bystander CD4+ T cell autophagy is dependent upon PI3KI. Overall, our data elucidate an important pathway linking TCR activation to autophagy, via induction of PI3KI activity and inositol phosphatase upregulation to produce PI(3)P.

Highlights

Autophagy is a major pro-survival mechanism, involved in intracellular remodeling and delivery of membrane-bound structures, termed autophagosomes, to the lysosome for turnover of the encompassed components into constituent building blocks (Bento et al, 2016)
Since kinase activity of the class III Phosphatidylinositol 3 Kinase (PI3K), Vps34, is dispensable for autophagy induction in T cells (McLeod et al, 2011), if not the entire protein itself (Willinger and Flavell, 2012), we investigated what other classes of PI3K were required for starvation-induced autophagy
Studies from our lab showing Vps34 kinase activity is dispensable for autophagy induction in T lymphocytes, suggest that other PI3K classes important

Summary

Introduction

Autophagy is a major pro-survival mechanism, involved in intracellular remodeling and delivery of membrane-bound structures, termed autophagosomes, to the lysosome for turnover of the encompassed components into constituent building blocks (Bento et al, 2016). Autophagy plays an important role in orchestrating innate and adaptive immune responses (Schmid and Munz, 2007; Cui et al, 2019). It plays specialized functions in antigen processing and presentation (Münz, 2016; Øynebråten, 2020), and thymic education. Vps has been shown to directly produce PI(3)P from phosphatidylinsotiol (PI), and has been demonstrated in several systems to be the major PI3K responsible for the production of cellular PI(3)P for autophagy (Yang and Van Kaer, 2020). It has been shown that Class I PI3K regulates autophagy by modulating protein synthesis and the Beclin 1 signaling pathway in malignant blood cells (Wang et al, 2017). This could be due in part to varying subcellular localizations or differing upstream receptors and adaptors

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