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Molecular mechanisms involved in redox-dependent regulation of endoplasmic reticulum-plasma membrane contacts

Grant number: 21/13257-6
Support Opportunities:Scholarships abroad - Research Internship - Post-doctor
Effective date (Start): July 04, 2022
Effective date (End): July 03, 2023
Field of knowledge:Health Sciences - Medicine - Medical Clinics
Principal Investigator:Francisco Rafael Martins Laurindo
Grantee:Tiphany Coralie de Bessa
Supervisor: Ajay Manmohan Shah
Host Institution: Instituto do Coração Professor Euryclides de Jesus Zerbini (INCOR). Hospital das Clínicas da Faculdade de Medicina da USP (HCFMUSP). Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil
Research place: King's College London, England  
Associated to the scholarship:18/07511-4 - Endoplasmic reticulum-plasma membrane contacts as hubs for NOx NADPH oxidase-dependent cellular redox signaling, BP.PD


Understanding molecular pathways involved in the redox regulation of endoplasmic reticulum-plasma membrane contacts (ER-PM) is an important goal for clarifying several aspects of the ER-related pathophysiology of Nox NADPH oxidases and, in particular, the interplay between PDIA1 and Noxes. Our group has previously described that PDIA1 is a major upstream regulator of Nox family, which are transmembrane enzymatic complexes accounting for most signaling reactive oxygen species in cells. Since both ER and PM are relevant PDIA1 and Nox subtype locations, we questioned whether ER-PM contacts might be preferential hubs for PDIA1/Nox cross talk. In our ongoing project we showed that PDIA1 and Nox1 are part of the ER-PM contacts and/or interact with structural ER-PM proteins such as Extended Synaptotagmin-3 (Esyt3), a tethering protein specific of ER-PM. We observed that induction of ER-PM contacts through forced Esyt3 expression induces impaired PDIA1 secretion, increased Nox1 Protein expression and an increased expression and isoform switch of Nogo-B protein, an ER curvature-shaping protein. Moreover, PDIA1 loss-of-function promoted ER-PM contact remodeling, with increased number of ER-PM contacts per cell but decreased size, accompanied by ER-shape remodeling and decreased NOGO-B protein expression. To understand the interplay of PDIA1 and Noxes at ER-PM contacts, we must advance further into the mechanistic dissection of our ongoing findings. The specific aims of our BEPE project are: Aim 1: To understand through imaging tools how the forced increase in ER-PM contacts affect Nox1 and Nox4 activity. Aim 2: To investigate the mutual interplay between calcium fluxes at ER-PM contacts and Nox activation by a combined approach to calcium/ROS imaging Aim 3: To investigate whether Nogo-B variants B1 and B2 play specific roles in ER-shaping or functional ER-PM contacts regulation and also whether PDIA1 and/or Noxes regulate Nogo-B variant expression. This BEPE will be performed in the laboratory of our collaborator Prof. Ajay Shah at King's College of London. The proposed collaboration may provide the first data on the possible importance of ER-PM contacts in redox/Nox-dependent signaling processes, as well as a novel mechanistic pathway for the interplay between ER-related functions such as calcium handling and oxidative processes. (AU)

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