# Non-canonical functions of autophagy proteins

> **NIH NIH R01** · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · 2020 · $448,750

## Abstract

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.

## Key facts

- **NIH application ID:** 9955166
- **Project number:** 5R01AI040646-23
- **Recipient organization:** ST. JUDE CHILDREN'S RESEARCH HOSPITAL
- **Principal Investigator:** Douglas R. Green
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $448,750
- **Award type:** 5
- **Project period:** 1997-05-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9955166

## Citation

> US National Institutes of Health, RePORTER application 9955166, Non-canonical functions of autophagy proteins (5R01AI040646-23). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9955166. Licensed CC0.

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