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

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 contr...

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Autores principales: McLeod, Ian X., Saxena, Ruchi, Carico, Zachary, He, You-Wen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8397451/
https://www.ncbi.nlm.nih.gov/pubmed/34458267
http://dx.doi.org/10.3389/fcell.2021.709398
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author McLeod, Ian X.
Saxena, Ruchi
Carico, Zachary
He, You-Wen
author_facet McLeod, Ian X.
Saxena, Ruchi
Carico, Zachary
He, You-Wen
author_sort McLeod, Ian X.
collection PubMed
description 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)P(2) 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.
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spelling pubmed-83974512021-08-28 Class I PI3K Provide Lipid Substrate in T Cell Autophagy Through Linked Activity of Inositol Phosphatases McLeod, Ian X. Saxena, Ruchi Carico, Zachary He, You-Wen Front Cell Dev Biol Cell and Developmental Biology 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)P(2) 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. Frontiers Media S.A. 2021-08-12 /pmc/articles/PMC8397451/ /pubmed/34458267 http://dx.doi.org/10.3389/fcell.2021.709398 Text en Copyright © 2021 McLeod, Saxena, Carico and He. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cell and Developmental Biology
McLeod, Ian X.
Saxena, Ruchi
Carico, Zachary
He, You-Wen
Class I PI3K Provide Lipid Substrate in T Cell Autophagy Through Linked Activity of Inositol Phosphatases
title Class I PI3K Provide Lipid Substrate in T Cell Autophagy Through Linked Activity of Inositol Phosphatases
title_full Class I PI3K Provide Lipid Substrate in T Cell Autophagy Through Linked Activity of Inositol Phosphatases
title_fullStr Class I PI3K Provide Lipid Substrate in T Cell Autophagy Through Linked Activity of Inositol Phosphatases
title_full_unstemmed Class I PI3K Provide Lipid Substrate in T Cell Autophagy Through Linked Activity of Inositol Phosphatases
title_short Class I PI3K Provide Lipid Substrate in T Cell Autophagy Through Linked Activity of Inositol Phosphatases
title_sort class i pi3k provide lipid substrate in t cell autophagy through linked activity of inositol phosphatases
topic Cell and Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8397451/
https://www.ncbi.nlm.nih.gov/pubmed/34458267
http://dx.doi.org/10.3389/fcell.2021.709398
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