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

E3 连接酶 UBR5 在 B 细胞发育和激活过程中选择性剪接中的作用

基本信息

批准号：
10297399
负责人：
Shannon Buckley
金额：
$ 38.54万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-25 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10297399
关键词：
Alternative Splicing Antibodies B-Cell Activation B-Cell Development B-Lymphocyte Subsets B-Lymphocytes C-terminal Cell Cycle Cell Maturation Cell physiology Cells Complex Cysteine DNA Damage DNA Repair Data Defect Development Down-Regulation Genetic Genetic Transcription Goals Hematopoietic Neoplasms Immune system Immunity Immunization Immunoglobulin Class Switching Immunoglobulin D Immunoglobulin Somatic Hypermutation Immunoglobulin Switch Recombination Immunologic Deficiency Syndromes Immunoprecipitation Length Ligase Lymphomagenesis Lymphopoiesis Malignant Neoplasms Mantle Cell Lymphoma Mediating Messenger RNA Molecular Mutant Strains Mice Mutate Natural Immunity PTPRC gene Pathway interactions Patients Phenotype Plasma Cells Play Population Process Proteins Proteomics RNA Splicing Regulation Role Signal Pathway Signal Transduction Spleen Spliceosomes Stream Structure of germinal center of lymph node Testing Transcript Transcriptional Regulation Translations Ubiquitin Up-Regulation V(D)J Recombination Variant adaptive immunity cell motility conditional mutant immune system function improved insight leukemia/lymphoma mutant novel overexpression peripheral blood plasma cell differentiation protein expression scaffold tool tumor ubiquitin ligase ubiquitin-protein ligase

项目摘要

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.

摘要