Estudio de la formina reguladora de la F- actina FMNL1 en el proceso de secreción polarizada de exosomas en la sinapsis inmune de linfocitos T humanos

Activation of the T-cell receptor (TCR) on a T lymphocyte (LT) is initiated by the presentation of an antigen via the major histocompatibility complex type II (MCHII) on an antigen-presenting cell (APAC). This interaction forms a dynamic structure known as the immune synapse (IS),This rearrangement occurs in three distinct zones: the central Supramolecular Activation Cluster (cSMAC), peripheral Supramolecular Activation Cluster (pSMAC), and distal Supramolecular Activation Cluster (dSMAC). During this reorganization, there is the creation of less-dense regions of cortical F-actin in the cSMAC while accumulation occurs in the outermost region (dSMAC). Simultaneously, multivesicular bodies (MVBs) aggregate around the Microtubule Organizing Center (MTOC), which polarizes towards the IS, resulting in the directional release of exosomes. This investigation examines the role fo the Formin Like-1 protein (FMNL1) in these processes. FMNL1 is essential for efficient directional transport, as its disruption leads to a reduction in less-dense F-actin areas and the polarization of the MTOC towards the IS. Formin Like-1β(FMNL1β) concentrates at he IS, and its presence restores the formation of less-dense F-actin areas and MTOC polarization. Additionally, both FMNL1 and FMNL1β coexist with cortical F-actin at the IS interface. The potential phosphorylation site within FMNL1β's autoregulatory domain, activating the formin, has been scrutinized. This project provides evidence supporting the idea that the protein kinase PKCδ phosphorylates the S1086 residue of FMNL1β. Substituting S1086 with a non-phosphorylatable amino acid results in diminished F-actin and reduced MTOC polarization towards the Is. Conversely, replacing S1086 with a phosphomimetic amino acid restores these effects. The study's outcomes suggest that FMNL1β plays a crucial role in the creation of less-dense cortical F-actin regions at the IS and the polarization of the MTOC towards the IS. It is proposed that these processes, critical for directional secretion, are modulated by phosphorylation of the C-terminal residue S1086 of FMNL1β