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

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2020 · $179,110

## 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:** 10135458
- **Project number:** 3R01GM087415-11S1
- **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:** $179,110
- **Award type:** 3
- **Project period:** 2010-05-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10135458

## Citation

> US National Institutes of Health, RePORTER application 10135458, Roles of the ER Stress Surveillance Pathway During the Cell Cycle (3R01GM087415-11S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10135458. Licensed CC0.

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