Functional convergence between lipid droplets, Nox4 and the ubiquitin-proteasome system during endoplasmic reticulum stress in vascular smooth muscle cells

• Grant number: 12/23361-6
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• Start date: April 15, 2013
• End date: April 14, 2014
• Field of knowledge: Biological Sciences - Biology
• Principal Investigator: Francisco Rafael Martins Laurindo
• Grantee: Thalita Balsamo Abrahão
• Supervisor: Kathy K. Griendling
• Host Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Institution abroad: Emory University, United States

Abstract

In a ER stress scenario, Nox4 expression and ROS-producing activity are increased, accounting, in a context-specific way, for either survival or apoptosis (Pedruzzi et al, 2004; Santos et al, 2009; Wu et al, 2010). The specific signaling pathways triggered by Nox4 in this situation are poorly known. ER stress is associated with the accumulation of un/misfolded proteins and toxic lipids within the ER lumen. An important defense mechanism parallel to the UPR is the ER-associated protein degradation (ERAD), in which defective proteins are retrotranslocated to the cytosol for proteasomal degradation, following their polyubiquitination or oxidation. In this process, LD, which bud from the ER, can serve as platforms for proteasomal delivery, behaving as escape hatches preventing protein aggregation (Hapala et al, 2011). Moreover, toxic lipids migrate to the lipid droplet core avoiding cytoplasm lipotoxicity. Our ongoing investigation indicates that (a) Nox4 sustains the pool of LD in vascular smooth muscle cells, (b) a fraction of Nox4 protein is present in LD, (c) proteasome inhibition enhances Nox4 levels; (d) the ER stressor tunicamycin promotes enhanced perinuclear LD clustering. We propose that: 1. Nox4 mediates polyubiquitinated protein flow to the proteasome through lipid droplets under ER stress condition, meaning that Nox4 contributes to sustained ERAD; and 2. Nox4 is transported to the proteasome through lipid droplets during ER stress. (AU)