A critical role for UBXN3B in IgG homeostasis and maternal transfer

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Immunoglobulin G (IgG) is the most abundant Ig and has a long half-life (~21 days in humans, ~7 days in mice) relative to other Ig and serum proteins. People with IgG deficiencies are vulnerable to microbial infections; however, the underlying causes are unknown. The serum IgG and albumin are continuously internalized by vascular endothelial cells, macrophages and dendritic cells through pinocytosis, then sorted partly to the lysosomes for degradation and partly recycled by the neonatal Fc receptor (FcRn) back to the blood circulation. Thus, FcRn is crucial for maintaining a normal serum IgG level by extending its half-life. It is also essential for maternal IgG transfer to fetuses, providing a crucial adaptive immune protection to fetuses. Herein we propose an important role for a UBX domain-containing protein (UBXN) in regulating the serum IgG recycling. Our preliminary studies demonstrated that the serum levels of antigen- specific and total IgG were reduced in Ubxn3b knockout mice when compared to their wild-type littermates; while the IgM levels were the same. Mechanistically, in vivo pulse-and-chase experiments showed that IgG was degraded much faster in the knockout mice than their littermates. In line with this, in vitro pulse-and- chase experiments showed that IgG was unable to be recycled in knockout cells. We thus hypothesize that UBXN3B is crucial for maintaining IgG homeostasis and it regulates FcRn-mediated IgG recycling and transcytosis. First, we will determine if the half-life of IgG subclasses is reduced, if maternal IgG transfer from the mother to fetus and across the intestinal epithelia is blocked in the knockout mice. Second, we will determine if IgG recycling and transcytosis is deficient in knockout cells, if FcRn-mediated IgG recycling/transcytosis is reliant on UBXN3B and if the cellular fate/ localization of IgG/ FcRn is altered in knockout cells. We hope to prove a critical role for UBXN3B in IgG recycling and maternal transfer and would establish a functional relationship between FcRn and UBXN3B. Our results from the mouse work could be also applicable to humans because the UBXN3B protein is highly conserved across species, and could provide an alternative therapeutic target for improving the serum half-life of therapeutic monoclonal antibodies or reducing the half-life of pathogenic antibodies. We hope that the results from this R21 will lay a solid foundation for more in-depth mechanistic and functional studies.