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

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2020 · $323,900

## Abstract

Project Summary
The accurate replication and proper division of the genome is essential to life, and “checkpoints” are
placed throughout the cell cycle to ensure accuracy. Much less is known about the presence of
checkpoints for the inheritance of functionally correct cytoplasmic organelles. The ER, a large and
essential organelle, generates virtually all secretory and transmembrane proteins, and most lipids of the
cell. We previously discovered a cell cycle checkpoint, the ER Stress Surveillance pathway (ERSU),
which is vital for the inheritance of functionally correct ER by daughter cells in the model organism S.
cerevisiae. When activated by ER stress, the ERSU pathway: (1) blocks the inheritance of damaged ER
by preventing the “initiating” ER tubule from entering the daughter cell, (2) mislocalizes the septin ring
from the site of cytokinesis, and ultimately, (3) leads to a cell cycle arrest until a functional ER can be re-
established. Cells that are mutant in the ERSU pathway die upon ER stress, underscoring the importance
of the ERSU. Notably, the ERSU pathway is distinct from the well known Unfolded Protein Response
(UPR). In the past grant period, in search of the signal that activates ERSU, we found that
phytosphingosine (PHS), an early intermediate of sphingolipid biosynthesis, is an ERSU activator. PHS
increases upon ER stress induction and, when exogenously added, PHS sets in motion all the ERSU
hallmark events. Moreover, we identified novel transmembrane domain mutants in Reticulon 1 (Rtn1), a
protein important for correct ER structure: these mutants inactivate ERSU without affecting overall ER
structure. In AIM 1, we will investigate how phytosphingosine activates the ERSU pathway. We also will
test how Reticulons are altered by PHS to prevent damaged ER inheritance. In AIM 2, we will investigate
how ER tubule inheritance is blocked at the molecular level, examining the role of key cell cycle structures
such as septins, cytoskeletal elements, the exocyst and polarisome. In AIM 3, we will: (A) Address
whether there is a mammalian ERSU pathway. Our observations of mislocalization of septins upon
mammalian ER stress provide initial compelling evidence. (B) Interrogate the impact of ER stress on the
mammalian cell cycle including major mitotic cell cycle structural changes that involve the ER, such as
ER clearing, nuclear disassembly and reassembly. Understanding the mechanisms by which the ER is
inherited in normal cells and how this is perturbed under stress conditions will contribute to our
understanding of human disease. Dysregulated ER function is a prominent feature of diabetes,
Alzheimer's and Parkinson's, key public health concerns. We hope our study will point towards new
treatments for such diseases.

## Key facts

- **NIH application ID:** 9978072
- **Project number:** 5R01GM087415-11
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Maho R Niwa
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $323,900
- **Award type:** 5
- **Project period:** 2010-05-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9978072

## Citation

> US National Institutes of Health, RePORTER application 9978072, Roles of the ER Stress Surveillance Pathway During the Cell Cycle (5R01GM087415-11). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9978072. Licensed CC0.

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