# The interplay between the UPR and protein biogenesis at the ER

> **NIH NIH R01** · YALE UNIVERSITY · 2024 · $77,144

## Abstract

Project Summary/Abstract:
Secretory and membrane proteins, which account for ~30% of all human proteins, are co-translationally
translocated across or inserted into the endoplasmic reticulum (ER). These nascent polypeptides are folded
into functional proteins with the help of chaperones and folding enzymes in the ER. Defects in protein folding
lead to the accumulation of misfolded proteins and the triggering of ER stress, which activates the unfolded
protein response (UPR). Of the three major UPR sensors, IRE1α is the most conserved ER-localized
transmembrane kinase/RNase that is activated through oligomerization/phosphorylation upon ER stress. Once
activated, IRE1α mediates the splicing of XBP1u mRNA to produce an active transcription factor, XBP1s,
which drives expression of UPR target genes to mitigate ER stress. Also, IRE1α promiscuously cleaves ER-
localized mRNAs through the regulated Ire1-dependent decay (RIDD) pathway to reduce the burden of the
incoming protein load. Under chronic ER stress conditions, however, IRE1α switches from the pro-survival
mode to pro-apoptotic mode, resulting in cell death, which is associated with human diseases including, type 2
diabetes and cancer. Despite the physiological importance, the factors that control activation and inactivation
of IRE1α/XBP1 signaling remain unclear.
 We have recently discovered that IRE1α forms a complex with the Sec61/Sec63 translocon complex to
access its mRNA substrates. In the current funding period, we have shown that the Sec61 translocon bridges
IRE1α with the Sec63/BiP complex to turnoff IRE1α signaling during persistent ER stress. Our studies
discovered that the Sec63/BiP complex is also responsible for freeing clogged Sec61 translocons as well as
promoting protein folding in the ER. These new findings raise the hypothesis that the IRE1α/Sec61/Sec63
complex plays a central role in the activation and inactivation of IRE1α/XBP1 signaling to maintain ER
homeostasis in cells. In the next funding period, we will test this hypothesis by (i) determining the role of this
complex in making life-or-death decisions during ER stress; (ii) determining the architecture of the
IRE1α/Sec61/Sec63/BiP complex; (iii) determining the role of this complex in sensing/responding to protein
translocation defects in the ER. In an independent aim, we will establish a novel functional link between a
cytosolic quality control and IRE1α/XBP1 signaling. We plan to use a combined approach of CRISPR/Cas9
edited cells, biochemical reconstitution, and structural approaches to address these problems. Overall, we
expect these studies will provide a mechanistic insight into how the UPR and protein translocation/quality
control pathways work together to maintain ER homeostasis. The knowledge gained from these studies will
inform the development of possible treatments for several human diseases including diabetes, cancer, and
polycystic liver diseases.

## Key facts

- **NIH application ID:** 10830294
- **Project number:** 5R01GM117386-09
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** MALAIYALAM MARIAPPAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $77,144
- **Award type:** 5
- **Project period:** 2016-06-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10830294

## Citation

> US National Institutes of Health, RePORTER application 10830294, The interplay between the UPR and protein biogenesis at the ER (5R01GM117386-09). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10830294. Licensed CC0.

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