Function of PERK in T cell metabolic reprogramming: deciphering its role as ER stress sensor vs its novel role as coordinator of membrane contact sites

Metabolic reprogramming plays a crucial role in T cell development, differentiation, and acquisition of effector functions. Inadequate metabolic fitness of T cells is a critical factor limiting the efficacy of immunotherapy for cancer therapy, highlighting the need for studies to improve our understanding of T cell metabolic regulation. Growing evidence indicates that metabolism is regulated at highly specialized sites of close appositions between the endoplasmic reticulum (ER) and other organelles, called membrane contact sites (MCS). However, both the key molecular effectors of MCSs and their role in the metabolism and function of T lymphocytes remain elusive. Our lab revealed that PERK, a member of the unfolded protein response (UPR) elicited by loss of ER homeostasis, has additional (UPR-independent) tethering functions, endorsing this protein kinase with the ability to coordinate MCSs. Our preliminary data show that PERK shapes T cell metabolism and effector functions. Here, I will use state of the art molecular/cellular biology tools, a recently developed microfluidic system, and transgenic mice with a specific deletion of Perk in T cells as in vivo models to study the role of PERK in T cell metabolic reprogramming and anti-tumor immunity, and decipher the mechanistic underpinnings related to its role as coordinator of MCSs or the UPR. Exploring the role of PERK as a relevant metabolic checkpoint in T cells may open new perspectives for T cell-based therapies.