Sunday, May 11, 2025
5/11/2025
Non-canonical functions of autophagy proteins - The ancient processes of phagocytosis and autophagy co-evolved as mechanisms of nutrient acquisition and pathogen defense, and under some circumstances their functional machineries intersect. This is the case for LC3-associated phagocytosis (LAP), a process in which some components of the autophagy pathway are recruited to the phagosome to lipidate LC3 molecules on this single membrane. LAP and canonical autophagy are distinct at the molecular, cellular, and organismal levels. Since we discovered this process eleven years ago, LAP has been implicated in immune responses to a variety of bacteria and fungi, and in several other physiological and disease settings. We have also identified a related, but distinct process of LC3-associated endocytosis (LANDO), which functions in the endocytosis of b-amyloid involved in Alzheimer’s Disease (AD). This application will explore the mechanisms of LAP and LANDO and their roles in myeloid responses in AD. We have chosen an AD model in which to interrogate the impact of LAP/LANDO defects in myeloid cells in vivo, and the core biochemistry of LAP in cell-free systems. We envision three aims of this project. 1. What are the mechanisms of LAP that distinguish it from conventional autophagy? Because LAP and autophagy share several molecular features, it is important to understand how LAP and autophagy are distinct at a molecular level. Here, we will explore the formation of the class 3 PI-3-kinase complex, unique to LAP, and how its activity recruits the ligase complex (common to LAP and autophagy) in a manner that is distinct from that of autophagy. 2. How does LANDO differ from conventional autophagy and LAP, and how does it influence cellular processes? We have identified a process, LANDO, distinct from LAP and autophagy, which nevertheless uses several of the proteins involved in each. We have found that this process is required for the recycling of several surface receptors to the plasma membrane following their internalization, even in non-phagocytic cells. We will interrogate LAP and autophagy proteins for their roles in LANDO and explore how these and other proteins known to be involved in receptor recycling influence cellular functions, including engulfment and inflammatory responses. 3. How do LAP and LANDO influence a model of Alzheimer’s Disease? Here, we will focus on the roles of LAP and LANDO in the clearance of amyloid by myeloid cells in the brain, and the consequences of defective LAP and/or LANDO for neuro-inflammation and degeneration. While studies of the decline of autophagic responses with age have been linked to disease, ours will be the first to do so in the context of these processes. LAP, LANDO, and autophagy share several molecular features but are distinct, and our studies proposed will reveal how these distinctions influence health and disease at the molecular, cellular, and organismal levels.
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