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Identification and characterization of novel molecular determinants of LC3-associated phagocytosis (LAP) in macrophages

Grant number: 19/26040-5
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): June 01, 2020
Effective date (End): May 31, 2023
Field of knowledge:Biological Sciences - Immunology - Cellular Immunology
Principal researcher:Larissa Dias da Cunha
Grantee:Edismauro Garcia Freitas Filho
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Associated research grant:18/25559-4 - Molecular mechanisms of LC3-associated phagocytosis and its role in macrophage function, AP.JP

Abstract

During phagocytosis, components of the autophagic machinery can associate with the phagosomal membrane in a process known as LC3-associated phagocytosis (LAP). This association occurs independently of the signaling pathways that trigger and regulate autophagy in response to nutritional stress, or macroautophagy, although the mechanisms regulating LAP are not well understood. In macrophages, LAP in response to pathogens not only controls phagolysosomal maturation and elimination of the invading microorganism, but also regulates phagosome-mediated innate signaling and cytokine production. LAP also occurs during the phagocytosis of dying cells (efferocytosis), controlling their degradation and regulating gene expression and cytokine production indicative of an anti-inflammatory, pro-tissue repair polarization program. This immunosuppressive role of LAP during efferocytosis protects the organism against development of autoimmunity, but it can also promote tumor tolerance. LAP possibly integrates phagocytosis to microenvironmental clues, regulating macrophage gene expression and functional polarization in different contexts. To determine the molecular mechanisms of LAP and how it diverges from macroautophagy is pivotal to characterize phagosome-autonomous effect on innate immune signaling, besides revealing novel potential pharmacological targets. Therefore, this study aims to identify and functionally characterize molecular components of LAP signaling transduction pathway, focusing on two main points. We will first investigate the role of the early endocytic pathway in the induction and maturation of the LAPosome. Secondly, we propose to use a recent alternative proteomic approach (TurboID-based proximity labeling) to identify and further characterize novel components of LAP pathway. (AU)

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