Mathematical Simulation of Linear Ubiquitination in T Cell Receptor-Mediated NF-κB Activation Pathway

Abstract

The linear ubiquitin chain assembly complex (LUBAC), composed of the HOIP, HOIL-1L, and SHARPIN subunits, activates the canonical nuclear factor-κB (NF-κB) pathway through the Met1 (M1)-linked linear ubiquitination activity. On the course of the T cell receptor (TCR)-mediated NF-κB activation pathway, LUBAC transiently associates with and linearly ubiquitinates the CARMA1-BCL10-MALT1 (CBM) complex. In contrast, the linear ubiquitination of NEMO, a substrate of the TNF-α-induced NF-κB activation pathway, was limited in the TCR pathway. A linear ubiquitin-specific deubiquitinase (DUB), OTULIN, plays a major role in downregulating LUBAC-mediated TCR signaling. Mathematical modeling indicated that linear ubiquitination of the CBM complex accelerates the activation of IκB kinase (IKK), as compared with the activity induced by linear ubiquitination of NEMO alone. Moreover, simulations of the sequential linear ubiquitination of the CBM complex suggested that the allosteric regulation of linear (de)ubiquitination of CBM subunits is controlled by the ubiquitin-linkage lengths. Thus, unlike the TNF-α-induced NF-κB activation pathway, the TCR-mediated NF-κB activation in T cells has a characteristic mechanism to induce LUBAC-mediated NF-κB activation.