An AMBRA1, ULK1 and PP2A regulatory network regulates cytotoxic T cell differentiation via TFEB activation

被引：0

作者：

Migliore, Loredana ^{[1
,7
]}

Cianfanelli, Valentina ^{[2
,7
]}

Zevolini, Fabrizia ^{[1
]}

Gesualdo, Monica ^{[1
]}

Marzuoli, Leandro ^{[1
]}

Patrussi, Laura ^{[1
]}

Ulivieri, Cristina ^{[1
]}

Marotta, Giuseppe ^{[3
]}

Cecconi, Francesco ^{[4
,5
,6
]}

Finetti, Francesca ^{[1
]}

Baldari, Cosima T. ^{[1
]}

机构：

[1] Univ Siena, Dept Life Sci, Siena, Italy

[2] Fdn Policlin Univ A Gemelli IRCCS, Dept Woman & Child Hlth & Publ Hlth, Gynecol Oncol Unit, Rome, Italy

[3] Siena Univ Hosp, Siena, Italy

[4] Univ Cattolica Sacro Cuore, Rome, Italy

[5] Fdn Policlin Univ Agostino Gemelli IRCCS, Rome, Italy

[6] Danish Canc Inst, Ctr Autophagy Recycling & Dis CARD, Cell Stress & Survival Grp, Copenhagen, Denmark

[7] Univ ROMA TRE, Dept Sci, Rome, Italy

来源：

SCIENTIFIC REPORTS | 2024年 / 14卷 / 01期

关键词：

AMBRA1; Cytotoxic T cell; Lytic granule /; PP2A; /; ULK1; INHIBITS AUTOPHAGY; LINKS AUTOPHAGY; MEMORY; MTOR; PROLIFERATION; EFFECTOR; KINASE; MECHANISM; PROTEIN; INNATE;

D O I：

10.1038/s41598-024-82957-9

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

The scaffold protein AMBRA1, which participates in the autophagy pathway, also promotes CD4+ T cell differentiation to Tregs independent of autophagy through its interactor PP2A. Here we have investigated the role of AMBRA1 in CD8+ T cell differentiation to cytotoxic T cells (CTL). AMBRA1 depletion in CD8+ T cells was associated with impaired expression of the transcription factors RUNX3 and T-BET that drive CTL differentiation and resulted in impaired acquisition of cytotoxic potential. These effects were recapitulated by pharmacological inhibition of the AMBRA1 activator ULK1 or its interactor PP2A. Based on the ability of PP2A to activate TFEB, we hypothesized a role for TFEB in the CTL differentiation program regulated by AMBRA1. We show that TFEB modulates RUNX3 and T-BET expression and the generation of killing-competent CTLs, and that AMBRA1 depletion, or ULK1 or PP2A inhibition, suppresses TFEB activity. These data highlight a role for AMBRA1, ULK1 and PP2A in CTL generation, mediated by TFEB, which we identify as a new pioneering transcription factor in the CTL differentiation program.

引用

页数：14

共 71 条

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