A model of autophagy size selectivity by receptor clustering on peroxisomes

TL;DR

This paper presents a computational model showing how receptor clustering on peroxisomes can enable size-selective autophagy, preferentially degrading larger organelles and explaining experimental observations.

Contribution

It introduces a novel mechanism where receptor clustering mediates size selectivity in autophagy, supported by computational simulations of peroxisome degradation.

Findings

Larger peroxisomes nucleate NBR1 clusters first

Size-selectivity favors degradation of larger organelles

Excess ubiquitin suppresses size-selectivity

Abstract

Selective autophagy must not only select the correct type of organelle, but also must discriminate between individual organelles of the same kind so that some but not all of the organelles are removed. We propose that physical clustering of autophagy receptor proteins on the organelle surface can provide an appropriate all-or-none signal for organelle degradation. We explore this proposal using a computational model restricted to peroxisomes and the relatively well characterized pexophagy receptor proteins NBR1 and p62. We find that larger peroxisomes nucleate NBR1 clusters first and lose them last through competitive coarsening. This results in significant size-selectivity that favors large peroxisomes, and can explain the increased catalase signal that results from siRNA inhibition of p62. Excess ubiquitin, resulting from damaged organelles, suppresses size-selectivity but not cluster formation. Our proposed selectivity mechanism thus allows all damaged organelles to be degraded, while otherwise selecting only a portion of organelles for degradation.