Orchestration of SARS-CoV-2 Nsp4 and host-cell ESCRT proteins induces morphological changes of the endoplasmic reticulum (Kifer et al 2025)

Orchestration of SARS-CoV-2 Nsp4 and host-cell ESCRT proteins induces morphological changes of the endoplasmic reticulum
Allison Kifer 1 , Franciso Pina 1 , Nicholas Codallos 1 , Anita Hermann 1 , Lauren Ziegler 1 , Maho Niwa 1
Affiliations
Affiliation

• 1 University of California, San Diego School of Biological Sciences Department of Molecular Biology NSB, Rm 5328 9500 Gilman Drive San Diego, CA 92093-0377.

• PMID: 39937675
• DOI: 10.1091/mbc.E24-12-0542

Abstract
Upon entry into the host cell, the non-structural proteins 3, 4, and 6 (Nsp3, Nsp 4, and Nsp6) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) facilitate the formation of double-membrane vesicles (DMVs) through extensive rearrangement of the host cell endoplasmic reticulum (ER) to replicate the viral genome and translate viral proteins. To dissect the functional roles of each Nsp and the molecular mechanisms underlying the ER changes, we exploited both yeast S. cerevisiae and human cell experimental systems.

Our results demonstrate that Nsp4 alone is sufficient to induce ER structural changes. Nsp4 expression led to robust activation of both the unfolded protein response (UPR) and the ER surveillance (ERSU) cell cycle checkpoint, resulting in cortical ER inheritance block and septin ring mislocalization. Interestingly, these ER morphological changes occurred independently of the canonical UPR and ERSU components but were mediated by the endosomal sorting complex for transport (ESCRT) proteins Vps4 and Vps24 in yeast.

Similarly, ER structural changes occurred in human cells upon Nsp4 expression, providing a basis for a minimal experimental system for testing the involvement of human ESCRT proteins and ultimately advancing our understanding of DMV formation.

 

Perhaps this could be part of the etiology of mecfs, a possible mechanism by which the "hit and run" theory could work:

The virus affects the endoplasmic reticulum in certain cells, such that the unfolded protein response is turned on. Even if the virus is gone or mostly gone some of its components might remain, activating ER stress. They even show that when stressed cells divide the new cell is stressed.

It also creates a possible explanation for PEM:

1. The body is meant to turn on the unfolded protein response on during exercise. But if the emergency system is already switched on and running, there's no further capacity to respond (nb here Hanson's study that showed mecfs bodies not responding to exercise).

The cells in question get overloaded with stress and a broader innate immune response is turned on. Pehaps if the stress is bad enough some of the cells in question go through apotosis or necrosis. If you like can assume the brain senses that in turn and activates still more protective sickness responses.

Just a theory and theories are cheap. But I would love to see more UPR testing in mecfs cells.

 

@Jonathan Edwards does this fit with the ‘internal cell memory’ that was discussed earlier (this week?)?

Could it be that there’s a gene-related error that leads to faulty cell memory which gets them stuck in an UPR state?

How would one go about testing this? Can we realibly ‘stress’ cells and see how they behave in various environments? E.g. plasma?