A transient Malt1 aggresome sustains T cell receptor signaling to NF-κB

Abstract

Abstract The T cell receptor (TCR) to NF-κB signaling pathway is crucial for T cell activation and differentiation. Upon engagement of the TCR with cognate antigen, a series of events leads to the formation of the Carma1-Bcl10-Malt1 (CBM) complex, increasingly recognized as vital to a properly functioning immune response. We have demonstrated that in effector T cells, the CBM complex gives rise to a polymeric, filamentous signalosome called POLKADOTS that directs terminal activation of NF-κB. POLKADOTS consist of the core protein Bcl10, its constitutive binding partner Malt1, and their recruited signaling partners. We have previously shown that Bcl10 is degraded via selective autophagy following T cell activation. Here, we show that Malt1, which serves both as an adaptor transmitting signals to NF-κB and as a protease which cleaves a variety of substrates, is not concurrently degraded. Instead, Malt1-containing POLKADOTS coalesce via microtubule transport to a canonical aggresome. Aggresomes are thought to be depots of misfolded protein destined for degradation via macroautophagy; however, the Malt1 aggresome promotes late stage NF-κB activation through prolonging pIKK-Malt1 interactions. Additionally, this aggresome enhances the proteolysis of a subset of Malt1 targets. These results establish a mechanism for sustaining cytoplasmic signals from the TCR. More broadly, our findings demonstrate that aggresomes can serve as a stable platform for signal transduction.