Intrinsic autophagy receptors: identity and cellular mechanisms.

Introduction

Macromolecular complexes (MC) are cellular machines that perform a wide array of vital tasks. They operate in a controlled, coordinated fashion within the crowded environment of the cell. Accumulation of dysfunctional MCs leads to age-related diseases.

Research Gap

Despite recent technological advancements, it still remains elusive for many of them how excess or dysfunctional MCs are sensed and removed. I have recently established a role of intrinsic receptors in the degradation of the nuclear pore complex and the clathrin-mediated endocytosis machinery by selective autophagy.

Role of Intrinsic Receptors

Intrinsic receptors represent functional subunits of the macromolecular machine but can, if needed, recruit the autophagy machinery to engulf and degrade the complex. As such, intrinsic receptors provide an in-built quality control function that monitors the assembly state and/or functionality of macromolecular machines.

Hypothesis

I hypothesize that this is a conserved and widely used principle existing within various MCs and that there is a common, yet unexplored, regulatory pathway underlying the intrinsic receptors’ mode of action.

Proposed Methodology

In the proposed project, I will employ a combination of:

1. Genetic screening
2. Mass spectrometry
3. Cryo-electron tomography

to systematically define intrinsic receptors and their working principles in cells.

Objectives

I will use systematic discovery approaches to determine:

1. How many MCs contain intrinsic receptors
2. How the degradation of intrinsic receptors and their cargo is regulated
3. How this is orchestrated with autophagosome biogenesis

Expected Outcomes

My results will not only provide insights into a novel cellular quality-control mechanism but also unravel novel aspects of selective autophagosome biogenesis.

Significance

Importantly, both accumulation of dysfunctional complexes and impairment of autophagy are linked to aging and age-related diseases. Therefore, my results will contribute to understanding the role of autophagy in these processes and have the potential to provide new pharmacological therapeutic avenues.