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

Area of Science:

• Immunology
• Cell Biology
• Molecular Biology

Background:

• T cell development relies on pre-T cell receptor and Notch signaling for β-selection.
• Maintaining proteostasis and TCR repertoire diversity during β-selection is crucial but poorly understood.

Purpose of the Study:

• To investigate the role of the endoplasmic reticulum-associated degradation (ERAD) machinery in T cell development.
• To elucidate the mechanisms by which ERAD regulates proteostasis during β-selection.

Main Methods:

• Investigated the SEL1L-HRD1 complex, a key ERAD component, in thymocyte development.
• Utilized genetic manipulation (e.g., deletion of Sel1l, inactivation of PERK and XBP1) in mouse models.
• Assessed thymocyte transition, apoptosis, and ER stress pathways (PERK, IRE1α/XBP1).

Main Results:

• SEL1L-HRD1 complex expression is regulated by Notch signaling.
• Sel1l deficiency impairs DN3 to DN4 thymocyte transition and αβ T cell development.
• Sel1l deficiency causes ER stress and apoptosis via the PERK pathway, which can be rescued by PERK inactivation.
• The IRE1α/XBP1 pathway acts as a compensatory mechanism, with its dual loss exacerbating defects.

Conclusions:

• ERAD machinery, specifically the SEL1L-HRD1 complex, acts as a critical proteostasis checkpoint during T cell β-selection.
• Notch-regulated ERAD is essential for preventing ER stress and ensuring proper thymocyte development.
• This study reveals a novel link between developmental signaling, proteostasis, and adaptive immunity.