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

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2024 · $333,617

## 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:** 10757414
- **Project number:** 5R01GM087415-14
- **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:** $333,617
- **Award type:** 5
- **Project period:** 2010-05-01 → 2026-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10757414

## Citation

> US National Institutes of Health, RePORTER application 10757414, Roles of the ER Stress Surveillance Pathway During the Cell Cycle (5R01GM087415-14). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10757414. Licensed CC0.

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