Serum amyloid A is a retinol binding protein that transports retinol during bacterial infection

Retinol plays a vital role in the immune response to infection, yet proteins that mediate retinol transport during infection have not been identified. Serum amyloid A (SAA) proteins are strongly induced in the liver by systemic infection and in the intestine by bacterial colonization, but their exact functions remain unclear. Here we show that mouse and human SAAs are retinol binding proteins. Mouse and human SAAs bound retinol with nanomolar affinity, were associated with retinol in vivo, and limited the bacterial burden in tissues after acute infection. We determined the crystal structure of mouse SAA3 at a resolution of 2 Å, finding that it forms a tetramer with a hydrophobic binding pocket that can accommodate retinol. Our results thus identify SAAs as a family of microbe-inducible retinol binding proteins, reveal a unique protein architecture involved in retinol binding, and suggest how retinol is circulated during infection. DOI: http://dx.doi.org/10.7554/eLife.03206.001 eLife digest Vitamins are nutrients that organisms require in order to survive and grow. If an organism is unable to synthesize a vitamin in sufficient quantities, it is essential that it obtain the vitamin through its diet instead. Vitamin A is found in foods such as eggs, animal liver and carrots, and a diet that is lacking in this vitamin can cause blindness and an increased risk of microbial infections. Vitamin A is not a single compound, but rather a collection of compounds with similar molecular structures. One of these is retinol, which plays a vital role in the body’s response to microbial infection. Retinol must bind to specific proteins to be able to move through the bloodstream and be transported around the body. Serum retinol binding protein transports ingested retinol from the intestine to the liver and other tissues. However, during microbial infection—when retinol transport is particularly important—the amount of this protein dramatically decreases; as such it is unclear how retinol is transported when the body is under attack from pathogens. It had been suggested that Serum Amyloid A (SAA) proteins, a family of proteins made by some liver and intestinal cells, could be involved in the response to infection, because these proteins’ levels increase during infection. However, their exact functions were unknown. Derebe, Zlatkov et al. found that mice fed a diet poor in vitamin A produced fewer SAA proteins in their liver and intestinal cells. However, treating the cells with retinol or the molecule it is broken down into—called retinoic acid—caused more SAAs to be made. Derebe, Zlatkov et al. also discovered that SAAs are associated with retinol in blood samples taken from mice infected with salmonella; and that both mouse and human SAAs bind tightly to retinol. Combined, this evidence suggests that SAAs are the retinol binding proteins that transport retinol during infections. Derebe, Zlatkov et al. went on to solve the crystal structure of a mouse SAA protein, and showed that four SAA molecules bind together to form a ‘pocket’ that can hold a retinol molecule. Future work will focus on understanding exactly how the transport of retinol by SAAs affects the development of immunity to infections. DOI: http://dx.doi.org/10.7554/eLife.03206.002