Unfolding the role of Perk in T cell biology and metabolism: a matter of contact sites?

The endoplasmic reticulum (ER) performs key cellular functions including protein and lipid synthesis/sorting, and calcium storage/signaling. To fulfil these functions the membranes of the ER physically connect with those of other organelles, like the mitochondria, through the agency of proteinaceous structures called membrane contact sites or MCSs. MCSs allow inter-organelle communication and are emerging as crucial signaling hubs for the spatial and temporal coordination of a variety of crucial cellular processes such as mitochondria bioenergetics and gene expression. However both the key molecular effectors of MCSs and their role in the metabolism and function of T lymphocytes remains elusive. Our work 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. Pilot experiments from our lab show that in T cells PERK shapes T cell metabolism and effector functions. To unfold the role of PERK as MCSs effector of T cell biology, here we will use state-of the art molecular/cellular biology tools, a recently developed microfluidics system and transgenic mice with a specific deletion of Perk in T cells as in vivo models to study its effects on anti-tumor immunity. We aim to define the relevance of PERK as main metabolic checkpoint in T cells, a finding that may open new perspectives for T cell based therapies.