# The Role of Pacs1-Wdr37 inLymphocyte Quiescence and Survival

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2024 · $410,000

## Abstract

PROJECT SUMMARY
 Naïve lymphocytes exist in a quiescent state until becoming activated by antigen. Their continued
survival depends on signals they receive through their antigen receptors and from homeostatic cytokines.
How naïve lymphocytes respond to pro-survival signals while continually maintaining quiescence is unclear.
This is an important issue: enhanced responses to survival signals can fuel malignant transformation while
impaired quiescence can trigger spontaneous immune activation and immune failure. We have recently
discovered a new protein complex containing phosphofurin acidic cluster sorting protein-1 (Pacs1) and WD
repeat protein 37 (Wdr37) that is required for normal lymphocyte survival and quiescence. Mice lacking
Pacs1 or Wdr37 were deficient in circulating B and T cells. Pacs1-Wdr37-deficient B cells exhibited
spontaneous proliferation in vivo coupled with increased apoptosis which indicated loss of cellular
quiescence. These cells demonstrated increased levels of endoplasmic reticulum stress in vitro and were
hypersensitive to oxidative stress. Importantly, Pacs1-Wdr37 deficiency did not impair humoral immune
responses. However, it potently suppressed lymphoproliferative diseases resulting from blocked apoptotic
pathways. Mechanistically, deletion of Pacs1 or Wdr37 impaired antigen receptor-dependent calcium (Ca2+)
release from the endoplasmic reticulum (ER) due to transcriptional downregulation of ER Ca2+ release
channels (inositol triphosphate receptors, IP3R). These results lead us to hypothesize that Pacs1-Wdr37
integrates antigen receptor-dependent Ca2+ signaling and cellular stress responses to promote lymphocyte
survival and quiescence. We will test this hypothesis by (i) elucidating how disruption of Pacs1-Wdr37
diminishes B cell survival and quiescence; (ii) defining how Pacs1-Wdr37 prevents ER stress and promotes
IP3R expression; and (iii) validating Pacs1-Wdr37 disruption as a therapeutic approach to B cell
malignancies.
Relevance to public health:
Signaling networks that permit lymphocyte survival are often co-opted during malignant transformation.
There is a need for therapies that subvert pro-survival signaling in diseased lymphocytes while preserving
most beneficial immune functions. This proposal will investigate a novel protein complex involved in
promoting lymphocyte survival and quiescence while preventing cell stress that is a promising therapeutic
target for lymphoid malignancies.

## Key facts

- **NIH application ID:** 10763029
- **Project number:** 5R01AI167920-03
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Evan Nair-Gill
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $410,000
- **Award type:** 5
- **Project period:** 2022-02-09 → 2027-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10763029

## Citation

> US National Institutes of Health, RePORTER application 10763029, The Role of Pacs1-Wdr37 inLymphocyte Quiescence and Survival (5R01AI167920-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10763029. Licensed CC0.

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