Función de la formina FMNL1 durante el tráfico secretor hacia la sinapsis inmunitari

Línea de investigación

Role of FMNL1 formin in polarized secretory traffic towards the immune synapse.

Descripción

T-cell receptor stimulation by antigen bound to the major histocompatibility complex (MHC) on an antigen-presenting cell (APC) induces protein kinase C (PKC) activation and the formation of the immune synapse (IS), followed by depletion of filamentous actin (F-actin) at the central region of the IS (cIS) and the polarization of multivesicular bodies (MVB) and the microtubule-organizing center (MTOC) to the IS. These events lead to polarized exosome secretion at the IS. These exosomes are involved in several crucial immune responses such as autocrine activation-induced cell death (AICD) of T lymphocytes and cytotoxicity by cytotoxic T lymphocytes (CTLs). Regarding the mechanisms controlling actin cytoskeleton in the IS, FMNL1 formin is located in the IS made by primary T lymphocytes, both in TCR and chimeric antigen receptor (CAR)-evoked synapses. We have shown that PKCdelta-dependent, formin-like 1 b (FMNL1beta) phosphorylation in S1086 results in formin activation leading to cortical actin reorganization and subsequent control of MTOC/MVB polarization and exosome secretion at the IS.

We will analyse how FMNL1beta regulates MTOC/MVB and mitochondria polarization at the IS in a phosphorylation-dependent manner, and we will analyse the consequences of FMNL1beta activation on T lymphocyte secretory function, including secretion and mitochondrial function. To this end, we will analyse polarized secretory traffic towards the IS in cells interfered in FMNL1 y re-expressing different FMNL1beta variants, including FMNL1βS1086A (non-phosphorylatable) and FMNL1βS1086D (phosphomimetic). The knowledge of the molecular bases underlying the traffic events involved in polarized secretion of pro-apoptotic exosomes, as well as mitochondrial function at the IS, will provide clues to modify crucial immune functions involving apoptosis, such as cytotoxicity by CTLs and immunoregulatory AICD and their associated pathologies, as well as it may allow to design therapeutic strategies to modify CAR T life spam, their exhaustion and/or polarized secretory function, in order to improve their efficiency for the treatment of certain cancers.

Contacto

Manuel Izquierdo Pastor.

Correo electrónico: manuel.izquierdo@inv.uam.es.

Departamento de Bioquímica (UAM).

Número de plazas ofertadas: 1.