Defining the role of Uba1 in bone marrow physiology and inflammation

New York University School Of Medicine, New York NY

Investigators

Abstract

PROJECT SUMMARY VEXAS (Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a newly identified severe autoinflammatory and hematologic disorder with high mortality caused by somatic mutations in UBA1. Estimated 1/14,000 people are affected by VEXAS syndrome in the US, yet there is no effective treatments and limited insight into pathogenic mechanisms to date. In this proposal, I will characterize the disease progression in the newly established VEXAS mouse models to investigate the molecular mechanisms of inflammation by loss of UBA1. UBA1 is an E1 enzyme responsible for initiating the majority of cellular ubiquitylation, and is essential for development. UBA1 mutations in VEXAS patients are acquired within hematopoietic stem cells (HSCs) and multipotent progenitor cells, but lineage-restricted in myeloid and mostly absent in lymphoid lineages. Our previous study showed that the most common UBA1 mutations result in loss of cytoplasmic isoform (UBA1b) and appearance of a catalytically deficient isoform (UBA1c), which correlated with decreased ubiquitylation and an increased in the unfolded protein response. Additional disease-causing mutations have revealed that hypomorphic activity of UBA1 can also lead to disease. There have been extensive efforts made by our lab and others to establish the VEXAS disease models from patients’ cells to study the mechanisms, but none of them was adequate to follow the progression of the disease. Loss of Uba1b in zebrafish resulted in upregulation in inflammatory signals recapitulating human disease, yet these animals die prematurely after birth, which imposes significant limitations in investigating the pathogenic mechanism of the disease. Therefore, it is necessary to establish the mouse models to recapitulate the somatic mutations in a cell type specific manner to analyze disease progression. We have recently generated and characterized the Uba1 transgenic mouse lines which conditionally removes all isoforms of Uba1 (Uba1flox/flox) and introduces VEXAS specific Uba1 mutation (Rosa26-Lox-Stop-Lox- Uba1M41V), mirroring the isoform swap present in humans, and have demonstrated that these animals have systemic inflammation. By removing UBA1 functions from HSCs and recapitulating VEXAS syndrome in these mouse models, I will define the role of UBA1 in bone marrow physiology and identify which blood lineages are dependent on Uba1 and cause inflammation (Aim1). I will further investigate the role of cytosolic isoform of UBA1, Uba1b, which is diminished in UBA1 mutant myeloid cells and inversely correlates with severity of VEXAS syndrome in patients (Aim2). Overall, the proposed project aims to advance our understanding of function of UBA1 in disease, which will provide the fundamental basis to build effective therapeutic strategy to treat VEXAS patients.