How cells control their organelles

A work published in the November issue of Nature Cell Biology by Fiorenza Fumagalli, Julia Noack, Timothy J. Bergmann et al. in the group of Maurizio Molinari at the Institute for Research in Biomedicine (IRB) identifies the translocon protein Sec62 as the autophagy receptor that regulates destruction of excess or damaged portions of the endoplasmic reticulum (ER), an intracellular organelle that produces proteins in our cells. The study also reveals that the newly discovered pathway relying on Sec62 function and named recovER-phagy is crucial to re-establish the function of the ER in cells that are recovering from acute ER stresses.

Half of the proteins circulating in our body, including all extracellular proteins, all proteins displayed at the cell surface, and all proteins operating in the endocytic and secretory pathways are synthesized in the ER. Maintenance of ER homeostasis even when cells do experience various type of physiologic (e.g., differentiation) or pathologic stress (e.g., expression of mutant gene products as in most inherited or sporadic rare conformational diseases, or pathogen attack) is crucial to ensure the production of the organism's proteome in appropriate quantity and quality.

Autophagy, a catabolic pathway regulating degradation of cellular materials (e.g., defective or old proteins) to re-cycle their building blocks, recently enjoyed the limelight with the 2016 Nobel Prize in Physiology and Medicine awarded to one of its discoverers, Yoshinori Ohsumi. Recently, a role of autophagy in clearance of defective organelles has been established. Damaged mitochondria, peroxisomes, intracellular organelles display specific autophagy receptors at their surface that trigger their selective delivery to autolysosomes for destruction. The work by Fumagalli et al. identified the receptor at the surface of the ER.

The accompanying News and Views article by Sebastian Schuck (Cell Network Cluster of Excellence and Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH), who was not involved in the study) and the highlights published by the Faculty of 1000 and by other journals (e.g., Nature Reviews Molecular Cell Biology) underline the importance of the work.

In fact, an involvement of autophagy in recovery from ER stresses impairing cell, tissue and organism viability had been proposed more than four decades ago and questions like "how do cells control the size of their organelles to keep them working" are important to understand (patho)physiological adaptation during growth, differentiation and disease.

"With the benefit of technological and scientific advances, the study by Molinari and colleagues has taken the concept of ER size control by ER-phagy to the molecular level". The comments also report that SEC62 is a candidate oncogene. It will be interesting to investigate whether the perturbation of ER homeostasis and aberrant recovER-phagy contribute to SEC62 overexpression-associated tumorigenesis.

Image

The central cell expresses high level of Sec62. This causes delivery of ER fragments (blue) into autolysosomes (their limiting membrane is stained in red with anti-Lamp1)