AMBRA1 is involved in T cell receptor-mediated metabolic reprogramming through an ATG7-independent pathway

Akatsuka, Hisako; Kuga, Shuhei; Masuhara, Kaori; Davaadorj, Odontuya; Okada, Chisa; Iida, Yumi; Okada, Yoshinori; Fukunishi, Nahoko; Suzuki, Takahiro; Hosomichi, Kazuyoshi; Ohtsuka, Masato; Tanaka, Masafumi; Inoue, Ituro; Kimura, Minoru; Sato, Takehito

doi:10.1016/j.bbrc.2017.08.019

Cited by 6 publications

(1 citation statement)

References 29 publications

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“…Sato et al. found that AMBRA1 regulates the activity of OVA53 precursor T cells and naive T cells in an autophagy-dependent manner ( 91 ). Furthermore, this group also found that AMBRA1 regulates the proliferation of precursor T cells and naive T cells in an autophagy-independent manner ( 92 ).…”

Section: Ambra1—a Potential Target For Anticancer Therapymentioning

confidence: 99%

AMBRA1 and its role as a target for anticancer therapy

Yuan

et al. 2022

Front. Oncol.

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The activating molecule in Beclin1-regulated autophagy protein 1 (AMBRA1) is an intrinsically disordered protein that regulates the survival and death of cancer cells by modulating autophagy. Although the roles of autophagy in cancer are controversial and context-dependent, inhibition of autophagy under some circumstances can be a useful strategy for cancer therapy. As AMBRA1 is a pivotal autophagy-associated protein, targeting AMBRA1 similarly may be an underlying strategy for cancer therapy. Emerging evidence indicates that AMBRA1 can also inhibit cancer formation, maintenance, and progression by regulating c-MYC and cyclins, which are frequently deregulated in human cancer cells. Therefore, AMBRA1 is at the crossroad of autophagy, tumorigenesis, proliferation, and cell cycle. In this review, we focus on discussing the mechanisms of AMBRA1 in autophagy, mitophagy, and apoptosis, and particularly the roles of AMBRA1 in tumorigenesis and targeted therapy.

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Section: Ambra1—a Potential Target For Anticancer Therapymentioning

confidence: 99%

AMBRA1 and its role as a target for anticancer therapy

Yuan

et al. 2022

Front. Oncol.

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

Migliore,

Cianfanelli,

Zevolini

et al. 2024

Sci Rep

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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.

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AMBRA1 controls antigen-driven activation and proliferation of naive T cells

Masuhara¹,

Akatsuka²,

Tokusanai³

et al. 2020

International Immunology

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AMBRA1 is a member of the BECN1 (BECLIN1) complex protein, and it plays a role in autophagy, cell death, tumorigenesis, and proliferation. We recently reported that on TCR stimulation, AMBRA1 controlled both autophagy and the cell cycle with metabolic regulation. Accumulating evidence has shown that autophagy and metabolic control are pivotal for T cell activation, clonal expansion, and effector/memory cell fate decision. However, it is unknown whether AMBRA1 is involved in T cell function under physiological conditions. We found that T cells in Ambra1-conditional knockout (cKO) mice induced exacerbated graft versus host response when they were transplanted into allogeneic BALB/c mice. Furthermore, Ambra1-deficient T cells showed increased proliferation and cytotoxic capability towards specific antigens in response to in vivo stimulation using allogeneic spleen cells. This enhanced immune response mainly contributed to naïve T cell hyperactivity. The T cell hyperactivity observed in this study were similar to those in some metabolic factor-deficient mice, but not those in other pro-autophagic factor-deficient mice. Under the static condition, however, naïve T cells were reduced in Ambra1-cKO mice, as same as in pro-autophagic factor-deficient mice. Collectively, these results suggested that AMBRA1 was involved in regulating T cell-mediated immune responses through autophagy-dependent and -independent mechanisms.

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AMBRA1 is involved in T cell receptor-mediated metabolic reprogramming through an ATG7-independent pathway

Cited by 6 publications

References 29 publications

AMBRA1 and its role as a target for anticancer therapy

AMBRA1 and its role as a target for anticancer therapy

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

AMBRA1 controls antigen-driven activation and proliferation of naive T cells

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