A20 Negatively Regulates T Cell Receptor Signaling to NF-κB by Cleaving Malt1 Ubiquitin Chains

Abstract

The Carma1-Bcl10-Malt1 signaling module bridges TCR signaling to the canonical IκB kinase (IKK)/NF-κB pathway. Covalent attachment of regulatory ubiquitin chains to Malt1 paracaspase directs TCR signaling to IKK activation. Further, the ubiquitin-editing enzyme A20 was recently suggested to suppress T cell activation, but molecular targets for A20 remain elusive. In this paper, we show that A20 regulates the strength and duration of the IKK/NF-κB response upon TCR/CD28 costimulation. By catalyzing the removal of K63-linked ubiquitin chains from Malt1, A20 prevents sustained interaction between ubiquitinated Malt1 and the IKK complex and thus serves as a negative regulator of inducible IKK activity. Upon T cell stimulation, A20 is rapidly removed and paracaspase activity of Malt1 has been suggested to cleave A20. Using antagonistic peptides or reconstitution of Malt1−/− T cells, we show that Malt1 paracaspase activity is required for A20 cleavage and optimal IL-2 production, but dispensable for initial IKK/NF-κB signaling in CD4+ T cells. However, proteasomal inhibition impairs A20 degradation and impedes TCR/CD28-induced IKK activation. Taken together, A20 functions as a Malt1 deubiquitinating enzyme and proteasomal degradation and de novo synthesis of A20 contributes to balance TCR/CD28-induced IKK/NF-κB signaling.

Critical role of PI3K signaling for NF-κB–dependent survival in a subset of activated B-cell–like diffuse large B-cell lymphoma cells

“…It has been shown that in T cells, MALT1 protease activity is required for optimal NF-κB activation and induction of target genes, but is dispensable for IKK/NF-κB upstream signaling (6,7). Thus, the stage of NF-κB activation controlled by PI3K-PDK1-MALT1 remains to be determined.…”

Expression, biological activities and mechanisms of action of A20 (TNFAIP3)

“…However, T-cells and B-cells constitutively express considerable high levels of A20, which inhibits ubiquitination of the NF-κB signaling protein MALT1 [70]. In this case, antigen 16 receptor stimulation triggers a rapid decrease and subsequent reappearance of A20, suggesting that A20 removal could be a crucial step in eliminating the negative regulatory activity of A20.…”

“…In this case, antigen 16 receptor stimulation triggers a rapid decrease and subsequent reappearance of A20, suggesting that A20 removal could be a crucial step in eliminating the negative regulatory activity of A20. Proteasomal degradation of A20, as well as its cleavage by the paracaspase MALT1, contribute to the decrease in A20, resulting in enhanced IL-2 production and NF-κB activation [70,71].…”

Regulation of T cell function by the ubiquitin-specific protease USP9X via modulating the Carma1-Bcl10-Malt1 complex

“…Previous studies have shown that the OTU domain-containing DUB A20 and the USP domain-containing DUB cylindromatosis protein negatively regulate NF-κB activation through deubiquitination of signaling molecules, such as RIP and TRAF2, in response to innate immune stimulation (5)(6)(7). In adaptive immunity, this is thought to involve ubiquitin-mediated regulation of key components of the T-cell receptor (TCR) signaling machinery, including the Carma1-Bcl10-Malt1 (CBM) complex (8) and Tak1 (9). How the deubiquitination system regulates the TCR-induced signaling pathway and T-cell function remains largely unclear, however.…”