ALG-2 couples T cell activation and apoptosis by regulating proteasome activity and influencing MCL1 stability

Tian-Sheng He,Jing Lu,Junqi Zhang,Wangsheng Ji,Xinqi Liu

doi:10.1038/s41419-019-2199-4

Abstract

T cell homeostasis is critical for the proper function of the immune system. Following the sharp expansion upon pathogen infection, most T cells die in order to keep balance in the immune system, a process which is controlled by death receptors during the early phase and Bcl-2 proteins in the later phase. It is still highly debated whether the apoptosis of T cells is determined from the beginning, upon activation, or determined later during the contraction. MCL1, a Bcl-2 family member, plays a pivotal role in T cell survival. As a fast turnover protein, MCL1 levels are tightly regulated by the 26S proteasome-controlled protein degradation process. In searching for regulatory factors involved in the actions of MCL1 during T cell apoptosis, we found that ALG-2 was critical for MCL1 stability, a process mediated by a direct interaction between ALG-2 and Rpn3, a key component of the 26S proteasome. As a critical calcium sensor, ALG-2 regulated the activity of the 26S proteasome upon increases to cytosolic calcium levels following T cell activation, this consequently influenced the stability of MCL1 and accelerated the T cell “death” process, leading to T cell contraction and restoration of immune homeostasis. Our study provides support for the notion that T cells are destined for apoptosis after activation, and echoes the previous study about the function of ALG-2 in T cell death.

Highlights

Introduction The abundance ofT lymphocytes in mammals is tightly regulated to ensure the proper function of the immune system
This study showed that following T cell activation, Apoptosis-linked gene 2 (ALG-2) enhanced the activity of the proteasome and promoted the degradation of MCL1 by a direct interaction with Rpn[3], coupling the T cell activation and apoptosis processes, shedding new light on the process of activation-induced cell death (AICD)
MCL1 protein levels were found to be stable in nutrient-efficient proliferating cells (Fig. 1b), but dramatically decreased in cells subjected to serum starvation, which was accompanied by an increase to cell death (Fig. 1b)

Summary

Introduction

T lymphocytes in mammals is tightly regulated to ensure the proper function of the immune system. Both an excess and lack of immune cells can lead to the malfunction of the immune system, reflected as either an auto immune disease or immunodeficiency. Antigen-specific T cells quickly proliferate by clonal expansion, resulting in a robust immune response against pathogen. Following the elimination of the pathogen, most of the T cells, except a small number with transition into memory cells, die through activation-induced cell death (AICD)[1,2]. Some evidences suggest that AICD is determined from the beginning of T cell activation, and T cell

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Conclusion