First responder to starvation: microreticulophagy clears aberrant membrane proteins in quick bites

Cells can use two different pathways for recycling their non-essential components in the lysosome during nutritional stress: macroautophagy and microautophagy. While the well-established macroautophagy pathway requires de novo formation of the double-membrane autophagosome, microautophagy involves direct engulfment of cargo by the lysosomal membrane. Recently, using a yeast model, we identified a novel microreticulophagy pathway induced by nutritional stress that selectively clears aberrant membrane proteins that accumulate during normal growth. This effective clearance occurs rapidly and precedes the degradation of normal ER- or mitochondrial-membrane proteins by macroautophagy. We showed that the nutritional-stress induced selective microreticulophagy pathway requires the ubiquitin-ligase Rsp5, its adaptor Ssh4, and the ESCRT complex. Moreover, live-cell fluorescence microscopy with high temporal and special resolution demonstrated that individual microautophagy events occur within seconds. Thus, cells use the effective microreticulophagy pathway to dispose of misfolded or excess membrane proteins as a first response to starvation. If the stress persists, the more costly macroautophagy pathway is activated for degrading normal cellular components. These findings point to an intricate interplay between microautophagy and macroautophagy during nutritional stress, which optimizes stress responses and could have significant implications for understanding how cells maintain homeostasis or progress to disease states.<b>Abbreviation:</b> ER, endoplasmic reticulum; ERAD, ER-associated degradation; QC, quality control; reticulophagy, selective autophagy of the ER.