# Roles of the ER Stress Surveillance Pathway During the Cell Cycle

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2024 · $67,422

## Abstract

Project Summary
To ensure that each dividing cell receives a complete set of the correct genome, cell cycle
checkpoints are in place throughout the cell cycle. Yet, less is known about whether similar
checkpoints exist for division of the cytoplasmic components or organelles of the cell. The
endoplasmic reticulum (ER) is a gateway for the secretory pathway, generating almost all of the
secreted and cell surface membrane proteins as well as synthesizing cellular lipids. Previously,
we identified a cell cycle checkpoint, termed the ER stress surveillance (ERSU) pathway, that
ensures the inheritance of sufficient levels of functional ER in the model organism S. cerevisiae.
In response to ER stress, the ERSU pathway (1) blocks the inheritance of the stressed ER into
the daughter cell, (2) mislocalizes the septin ring from the bud neck, the site of cytokinesis, and
ultimately, (3) leads to temporary cell cycle arrest at cytokinesis until ER functional homeostasis
is re-established. Cells that lack components of the ERSU, and thus cannot mount the ERSU
pathway, die upon ER stress, underscoring the importance of this checkpoint. The ERSU pathway
is distinct from the well-studied unfolded protein response. We have found that levels of
phytosphingosine (PHS), an early intermediate of sphingolipid biosynthesis, increase upon ER
stress, setting in motion the ERSU hallmark events. Moreover, we defined a PHS binding motif
that is found within two different transmembrane domains of reticulon family proteins (i.e., Rtn1
and Yop1), leading to the activation of the ERSU events. In the current proposal, in AIM 1, we will
apply molecular and cell biological approaches to dissect how PHS binding to Rtn1 or Yop1
results in ERSU activation. In AIM 2, we will extend the scope of the ERSU by dissecting the
impact of ER lipotoxic stress induced by ER morphological changes, on the ERSU molecular
events. In AIM 3, we will investigate how ER stress impacts the mammalian cell cycle. As the
nuclear membrane breaks down during mitosis in mammalian cells, the division of functional ER
may be even more tightly choreographed with the nuclear mitotic mechanisms. Our preliminary
result of a mammalian septin subunit holds great promise for the presence of regulatory events
that may share similarity to the yeast ERSU. Thus, we will fully investigate the impact of ER stress
on (A) the mammalian septin subunits and cytokinetic components, and (B) major mitotic cell
cycle structural changes that involve the ER, such as ER clearing from the “mitotic exclusion
zone” and nuclear disassembly and reassembly. Understanding the molecular mechanisms that
integrate ER homeostasis with cell cycle events will provide unprecedented insights into human
diseases caused by the failure of ER regulation.

## Key facts

- **NIH application ID:** 10887331
- **Project number:** 3R01GM087415-14S1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Maho R Niwa
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $67,422
- **Award type:** 3
- **Project period:** 2010-05-01 → 2026-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10887331

## Citation

> US National Institutes of Health, RePORTER application 10887331, Roles of the ER Stress Surveillance Pathway During the Cell Cycle (3R01GM087415-14S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10887331. Licensed CC0.

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