# Novel unconventional myosins in B cell homeostasis

> **NIH NIH R01** · CLEVELAND CLINIC LERNER COM-CWRU · 2024 · $529,302

## Abstract

ABSTRACT
Incurable autoimmune diseases afflict millions of Americans, cause pain and persistent damage to multiple organ
systems, and have a major impact on patient health, well-being and quality of life. Increased B cell numbers,
greater B cell activation and differentiation into plasma cells, and autoantibody production often characterize
autoimmunity, signifying that dysregulated B cell survival and differentiation are critical steps in autoimmune
pathogenesis. Identification of proteins and molecular events that regulate B cell survival, activation and
differentiation is therefore critical for better mechanistic understanding of autoimmune disease
development. Myo18A is a scaffolding protein with a unique domain organization that enables assembly of
multiprotein complexes in various subcellular compartments of non-immune cells. We reported that B cells
express Myo18A, and that its conditional deletion in B cells (Myo18A BKO) leads to an increase in mature B
cells and plasma cells, splenomegaly, hypergammaglobulinemia, and development of autoantibodies.
Interestingly, this profile overlaps with autoimmune manifestations reported in transgenic mice overexpressing
the B cell survival factor BAFF, and in mice with genetic deletion of proteins involved in mRNA decay. In
preliminary data, we observed that Myo18A-deficient B cells display features of greater BAFF responsiveness,
including increased mitochondrial size and gene expression, and stronger pro-survival Akt signaling, indicating
that Myo18A negatively regulates B cell response to BAFF. Additionally, deletion of Myo18A in B cells increased
the basal expression and reduced the decay of mRNA encoding Blimp-1, a key transcription factor in B cell
differentiation. Further, Myo18A in B cells bound to Blimp1 mRNA and co-localized with subcellular mRNA
degradation sites, indicating that Myo18A is involved in post-transcriptional regulation and expression of Blimp-
1. Our published and preliminary data suggest that Myo18A is an important and previously unrecognized
determinant in B cell immunity. Our specific aims are to test the hypotheses that (1) Myo18A restricts BCR
and BAFF-R signaling to control B cell homeostasis, (2) Myo18A inhibits mRNA stability to inform B cell gene
expression, and (3) Myo18A limits B cell differentiation by controlling the B cell transcriptome. The proposed
research is innovative because it will establish a novel role for the unconventional myosin family protein Myo18A
in preventing uncontrolled B cell activation and differentiation. Specifically, our research will identify a novel
functional connection between Myo18A and B cell survival and differentiation through regulation of B cell antigen
and BAFF responsiveness and post-transcriptional mRNA stability. This research is expected to have
significant impact because it will enable better mechanistic understanding of the molecular processes that
prevent exaggerated antibody development.

## Key facts

- **NIH application ID:** 10848359
- **Project number:** 5R01AI172916-02
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** Neetu Gupta
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $529,302
- **Award type:** 5
- **Project period:** 2023-06-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10848359

## Citation

> US National Institutes of Health, RePORTER application 10848359, Novel unconventional myosins in B cell homeostasis (5R01AI172916-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10848359. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*