Project: Understanding the functional impact of eif2ak mutants in dendritic cell and interferonopathies

About

The integrated stress response (ISR) is a cellular pathway activated by various biochemical triggers. It reduces global protein synthesis while promoting stress resolution and cell survival through the activation of different kinases of the eukaryotic translation initiation factor 2A (eIF2AK).

In immune imbalances, plasmacytoid dendritic cells (pDCs), monocytes, and B cells may fuel autoimmunity through the abnormal release of cytokines, type-I interferon (IFN), and autoantibodies. Recent research shows that ISR mediators, such as eIF2AK3 (PERK), can activate innate sensors (e.g., stimulator of interferon genes – STING) to induce type-I IFN production in response to nucleic acids or toxins. Notably, novel variants in genes encoding different eIF2A kinases and phosphatases have been identified in patients with autoimmune and autoinflammatory syndromes.

This project will investigate whether familial variants in the ISR genes may predispose individuals to disease.