Browsing by Subject "Serum Amyloid A Protein"
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Item Epithelial Retinoic Acid Receptor Beta Regulates Serum Amyloid A Expression and Vitamin A-Dependent Intestinal Immunity(2018-08-21) Gattu, Sureka; Winter, Sebastian E.; Kliewer, Steven A.; Hooper, Lora V.; Shiloh, MichaelVitamin A is a dietary component that is essential for the development of intestinal immunity. Vitamin A is absorbed and converted to its bioactive derivatives retinol and retinoic acid by the intestinal epithelium, yet little is known about how epithelial cells regulate vitamin A-dependent intestinal immunity. Here I show that epithelial cell expression of the transcription factor retinoic acid receptor β (RARβ) is essential for vitamin A-dependent intestinal immunity. Epithelial RARβ activated vitamin A-dependent expression of serum amyloid A (SAA) proteins by binding directly to Saa promoters. In accordance with the known role of SAAs in regulating Th17 cell effector function, epithelial RARβ promoted IL-17 production by intestinal Th17 cells. More broadly, epithelial RARβ was required for the development of key vitamin A-dependent adaptive immune responses, including CD4+ T cell homing to the intestine and the development of immunoglobulin A-producing intestinal B cells. My findings provide insight into how the intestinal epithelium senses dietary vitamin A status to regulate adaptive immunity and highlight the role of epithelial cells in regulating intestinal immunity in response to diet.Item Serum Amyloid A is a Retinol Binding Protein that Transports Retinol during Bacterial Infection(2014-07-17) Zlatkov, Clare Marie; Farrar, J. David; Hooper, Lora V.; Kliewer, Steven A.; Pasare, ChandrashekharRetinol plays a vital role in the immune response to infection, however it remains unclear which proteins mediate retinol transport during infection. Serum amyloid A (SAA) proteins are produced by the liver following acute systemic infection and are also induced by bacteria in the intestine. SAAs have been proposed to play a role in the inflammatory response to infection and injury, but their exact functions have not been well defined. In this dissertation, I present data that demonstrates the acute phase protein SAA is a novel retinol binding protein that transports retinol during infection. SAA proteins are induced by bacteria and additionally require retinol for their expression. I demonstrate that SAA’s requirement for retinol is not restricted to the small intestine, as mice on a vitamin A deficient diet have reduced SAA expression in the liver as well. Additionally, I demonstrate in fluorescence based binding assays that SAAs are capable of binding retinol at nanomolar affinities, which is comparable to a known retinol binding protein. I also found that SAA proteins associate with retinol in the serum following a bacterial challenge in wild-type mice. This phenotype was not observed in SAA1/2-/- mice following bacterial challenge. Furthermore, SAA1/2-/- mice have greater bacterial loads in their spleens and livers following bacterial infection. In parallel with my studies, Dr. Mehabaw Derebe, a post-doctoral researcher in the Hooper lab, recently solved the mSAA3 crystal structure, demonstrating the protein oligomerizes to form a tetramer. This tetramer unit contains a central pore-like cavity, lined with hydrophobic amino acid residues, which would allow a lipophilic ligand to bind. A single amino acid mutation within this hydrophobic core resulted in reduced mSAA3 retinol binding. This structural insight describes how SAA, as a small and mostly alpha-helical protein, can protect a lipophilic ligand from the aqueous environment. Altogether, these data demonstrated that SAAs are a family of microbe-induced retinol binding proteins, reveal a unique protein architecture involved in retinol binding, and provide insight into the acute response to infection.