T Cell Receptor–Dependent Activation of mTOR Signaling in T Cells Is Mediated by Carma1 and MALT1, But Not Bcl10

Abstract

Signaling to the mechanistic target of rapamycin (mTOR) regulates diverse cellular processes, including protein translation, cellular proliferation, metabolism, and autophagy. These effects are mediated in part by the mTOR targets S6 kinase (S6K) and eukaryotic initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1). Most models place Akt upstream of the best-studied mTOR complex, mTORC1; however, studies have called into question whether Akt is necessary for this pathway, at least in T cells. We found that the adaptor protein Carma1 [caspase recruitment domain (CARD)-containing membrane-associated protein 1 (Carma1)] and at least one of its associated proteins, the paracaspase MALT1 (mucosa-associated lymphoid tissue lymphoma translocation protein 1), were required for optimal activation of mTOR in T cells in response to stimulation of the T cell receptor (TCR) and the coreceptor CD28. However, another common binding partner of Carma1 and MALT1, Bcl10, was not required for TCR-dependent activation of the mTOR pathway. Consistent with these findings, MALT1 activity was required for the proliferation of CD4 + T cells, but not early TCR-dependent activation events. Also consistent with an effect on mTOR, MALT1 activity was required for the increased metabolic flux in activated CD4 + T cells. Together, our data suggest that Carma1 and MALT1 play previously unappreciated roles in the activation of mTOR signaling in T cells after engagement of the TCR.

Regulation of T cells by mTOR: the known knowns and the known unknowns

“…Discovering this kinase, presumably one or more additional AGC (camp-dependent, cGMP-dependent, and protein kinase C) kinases similar to Akt, S6K1 or SGK1 that can act in lieu of Akt, would reveal this precise mechanism and provide important insight in terms of better understanding the activation of mTOR in T cells and in general. Interestingly, one study suggests that MALT1 and Carma1, adaptor proteins that are known to complex with Bcl10 to activate NF-κB, may directly regulate mTORC1 without the necessity of Akt [33]. …”

Unexpected positive control of NFκB and miR-155 by DGKα and ζ ensures effector and memory CD8+ T cell differentiation

“…DAG associates with and allosterically activates RasGRP1 and PKCθ, leading to the activation of the Ras-Erk1/2-AP1 and CARMA1/Bcl10/MALT-IKK-NFκB signaling pathways that are indispensable for T cell activation and effector/memory CD8 T cell differentiation [8–11]. Additionally, the Ras-Mek1/2-Erk1/2 pathway and CARMA1 mediate TCR-induced mTOR activation [12, 13]. mTOR and its tight regulation by TSC1/2 have also been found to control effector/memory CD8 T cell fate decisions [14–18].…”

Congrès de l’association américaine de recherche contre le cancer — AACR 2015

“…La stimulation antigénique du récepteur du lymphocyte T (TCR) induit une activation de complexes protéiques (c'est-à-dire complexe CARMA1 [caspase recruitment domain (CARD)-containing membrane-associated protein 1], MALT1 [mucosa-associated lymphoid tissue lymphoma translocation protein 1]) permettant l'activation de mTOR [6]. Cette activation de mTOR requiert en plus du complexe CBM (CARMA1, BCL10, MALT1) [7] le transporteur de la glutamine ASCT2 (amino acid transporter 2) [8].…”