Notch-induced endoplasmic reticulum-associated degradation governs mouse thymocyte β-selection.

Xia Liu,Michael Y Zhao,Jingjing Yu,Katharine Umphred-Wilson,Brendan M Barton,Ling Qi,Xiangdong Lv,Yao Ding,Stanley Adoro,Fanglue Peng,Shengyi Sun,Yuning Hong,Longyong Xu,Xi Chen

doi:10.7554/elife.69975

Abstract

Signals from the pre-T cell receptor and Notch coordinately instruct β-selection of CD4-CD8-double negative (DN) thymocytes to generate αβ T cells in the thymus. However, how these signals ensure a high-fidelity proteome and safeguard the clonal diversification of the pre-selection TCR repertoire given the considerable translational activity imposed by β-selection is largely unknown. Here, we identify the endoplasmic reticulum (ER)-associated degradation (ERAD) machinery as a critical proteostasis checkpoint during β-selection. Expression of the SEL1L-HRD1 complex, the most conserved branch of ERAD, is directly regulated by the transcriptional activity of the Notch intracellular domain. Deletion of Sel1l impaired DN3 to DN4 thymocyte transition and severely impaired mouse αβ T cell development. Mechanistically, Sel1l deficiency induced unresolved ER stress that triggered thymocyte apoptosis through the PERK pathway. Accordingly, genetically inactivating PERK rescued T cell development from Sel1l-deficient thymocytes. In contrast, IRE1α/XBP1 pathway was induced as a compensatory adaptation to alleviate Sel1l-deficiency-induced ER stress. Dual loss of Sel1l and Xbp1 markedly exacerbated the thymic defect. Our study reveals a critical developmental signal controlled proteostasis mechanism that enforces T cell development to ensure a healthy adaptive immunity.

Highlights

; Michie and Zúñiga-Pflücker, 2002)
To maintain proteostasis and normal cell function, cells have evolved highly sensitive and sophisticated quality control systems to ensure the fidelity of protein structure, which is especially important for thymocytes undergoing b-selection that must repair protein damage and generate a functional and diverse repertoire of T cell receptors with high fidelity (Feige et al, 2015; Feige and Hendershot, 2013)
These observations suggested that the DN3-to-DN4 transition, which is initiated by b114 selection, is accompanied by induction of proteome quality control mechanisms

Summary

Introduction

; Michie and Zúñiga-Pflücker, 2002). In addition to cell autonomous signal through the pre-TCR, β-selection requires signal from the Notch receptor (Ciofani and Zúñiga-Pflücker, 2005; Sambandam et al, 2005). To maintain proteostasis and normal cell function, cells have evolved highly sensitive and sophisticated quality control systems to ensure the fidelity of protein structure, which is especially important for thymocytes undergoing b-selection that must repair protein damage and generate a functional and diverse repertoire of T cell receptors with high fidelity (Feige et al., 2015; Feige and Hendershot, 2013) Two such systems conserved across different species are ER-associated degradation (ERAD) and the unfolded protein response (UPR) (Figure 1 - figure supplement 1A) (Brodsky, 2012; Hwang and Qi, 2018; Walter and Ron, 2011). PERK-dependent eIF2a phosphorylation and subsequent increased cap-independent translation of ATF4 and induction of CHOP (Figure 1 - figure supplement 1A) (Hwang and Qi, 2018; Walter and Ron, 2011)

Methods

Results

Conclusion