Wednesday, August 6, 2025 8/6/2025

The interplay between the UPR and protein biogenesis at the ER

Award Number: R01GM117386
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2016
PERIOD OF PERFORMANCE END DATE: 04/30/2026

Group Awards By:

View Award Description

The interplay between the UPR and protein biogenesis at the ER - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = -$19,993 )
2025	2024	TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER	3601 4TH ST	LUBBOCK	TX	79430	LUBBOCK	USA	Biomedical Research and Research Training	003	10	3/20/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$789
2025	2024	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Biomedical Research and Research Training	000	9	11/18/2024	NON-COMPETING CONTINUATION	-$267,906
2025	2024	TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER	3601 4TH ST	LUBBOCK	TX	79430	LUBBOCK	USA	Biomedical Research and Research Training	001	10	11/19/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$247,913
2025	2024	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Biomedical Research and Research Training	002	9	3/20/2025	NON-COMPETING CONTINUATION	-$789
														Subtotal = -$19,993

Issue Date FY: 2024 ( Subtotal = $345,050 )
2024	2024	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Biomedical Research and Research Training	001	9	6/25/2024	NON-COMPETING CONTINUATION	$34,505
2024	2024	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Biomedical Research and Research Training	000	9	4/16/2024	NON-COMPETING CONTINUATION	$310,545
														Subtotal = $345,050

Issue Date FY: 2023 ( Subtotal = $345,050 )
2023	2023	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Biomedical Research and Research Training	000	8	4/19/2023	NON-COMPETING CONTINUATION	$345,050
														Subtotal = $345,050

Issue Date FY: 2022 ( Subtotal = $345,050 )
2022	2022	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Biomedical Research and Research Training	001	7	4/27/2022	NON-COMPETING CONTINUATION	$345,050
2022	2020	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Biomedical Research and Research Training	000	5	11/2/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $345,050

Issue Date FY: 2021 ( Subtotal = $345,050 )
2021	2021	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Biomedical Research and Research Training	000	6	5/10/2021	COMPETING CONTINUATION	$345,050
														Subtotal = $345,050

Issue Date FY: 2020 ( Subtotal = $330,813 )
2020	2020	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Biomedical Research and Research Training	000	5	5/18/2020	NON-COMPETING CONTINUATION	$330,813
														Subtotal = $330,813

Issue Date FY: 2019 ( Subtotal = $330,813 )
2019	2019	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Biomedical Research and Research Training	000	4	5/31/2019	NON-COMPETING CONTINUATION	$330,813
														Subtotal = $330,813

Issue Date FY: 2018 ( Subtotal = $330,813 )
2018	2018	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Biomedical Research and Research Training	000	3	5/15/2018	NON-COMPETING CONTINUATION	$330,813
														Subtotal = $330,813

Issue Date FY: 2017 ( Subtotal = $330,813 )
2017	2017	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Biomedical Research and Research Training	000	2	6/13/2017	NON-COMPETING CONTINUATION	$330,813
														Subtotal = $330,813

Issue Date FY: 2016 ( Subtotal = $330,648 )
2016	2016	YALE UNIVERSITY	47 College Street	NEW HAVEN	CT	06520	SOUTH CENTRAL CT	USA	Biomedical Research and Research Training	000	1	4/21/2016	NEW	$330,648
														Subtotal = $330,648

Grand Total All Awards = $3,014,107

Top

All Categories

About

Search

Reports

Data Submission

Award Information

The interplay between the UPR and protein biogenesis at the ER

Award Number: R01GM117386

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 06/01/2016

PERIOD OF PERFORMANCE END DATE: 04/30/2026

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer