# Role of E3 Ligase UBR5 in Alternative Splicing during B Cell Development and Activation

> **NIH NIH R01** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2021 · $385,386

## Abstract

ABSTRACT
 Proper B cell development is an essential part of innate and adaptive immunity. Coordination of a
number of molecular mechanisms are required to facilitate B cell development, maturation, activation, and
survival of B cells. Recently, the ubiquitin E3 ligase, UBR5 has been found mutated in a significant number of
cases of patients with mantle cell lymphoma, implicating the E3 ligase in B cell development. UBR5 is a key
regulator of DNA damage repair, transcription, translation, and our data suggests mRNA splicing via the
spliceosome. UBR5 is a HECT domain ligase, which contains a cysteine residue that is responsible for
ubiquitin transfer to its substrates. To elucidate the role of UBR5 in B cell maturation and activation we
generated a conditional mutant disrupting the C-terminal HECT domain. Loss of the HECT domain leads to a
block in maturation of B cells in the spleen with a reduction of B1 and marginal B cell subsets, as well as
phenotypic alterations and functional defects of follicular B cells. Proteomic studies reveal up-regulation of
spliceosome proteins in B cells lacking the HECT domain of UBR5, and that UBR5 interacts with splicing
factors. To further understand the functional role of UBR5 in regulating B cells activation and maturation and
the consequences of aberrant spliceosome component expression, we will define the role of UBR5 during
germinal center formation and activation (Aim 1), determine the ubiquitin independent vs. dependent function
in B cells (Aim2), and identify the role of spliceosome and altered transcripts in B cell activation (Aim 3). These
studies will unravel a novel role of UBR5 in B cell maturation by regulating alternative splicing of key transcripts
during B cell development.

## Key facts

- **NIH application ID:** 10297399
- **Project number:** 1R01AI153090-01A1
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** Shannon Buckley
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $385,386
- **Award type:** 1
- **Project period:** 2021-08-25 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10297399

## Citation

> US National Institutes of Health, RePORTER application 10297399, Role of E3 Ligase UBR5 in Alternative Splicing during B Cell Development and Activation (1R01AI153090-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10297399. Licensed CC0.

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