SALSA—A dance on a slippery floor with changing partners

Abstract

It is becoming increasingly clear that the connections between our immune system and the microbiota colonizing us have a tremendous impact on human health. A number of innate molecular defence mechanisms cooperate to selectively target unwanted microorganisms at the mucosal surfaces. Amongst others these include the complement system, IgA and the SALSA molecule. The salivary scavenger and agglutinin (SALSA), also known as deleted in malignant brain tumors 1 (DMBT1), salivary agglutinin (SAG) or gp340 is a multifunctional molecule with important functions in innate immunity, inflammation and epithelial homeostasis. The SALSA protein is expressed at most mucosal surfaces, where it is one of the most abundant proteins. In the fetal meconium and infant intestine it may constitute even up to 10% of the total protein amount. SALSA is found either directly associated with the epithelial surface or secreted into the lining fluids. In the fluid-phase SALSA interacts with a number of bacterial and viral organisms, as well as with endogenous ligands, including IgA, lactoferrin, surfactant proteins and complement components. While complement has been shown to impact the mucosal environment, this remains an area of limited research. The multiple interactions of the SALSA molecule provide a scaffold, where this potent defence system may engage in cooperative microbial clearance together with corresponding mucosal host ligands. With its high abundance, and multiple effects on both host and microbes, the SALSA molecule is a key player in maintaining the immunological balance at the mucosal surfaces. This is further supported by observations linking the expression of different SALSA isoforms to the development of chronic inflammatory conditions, such as Crohn's disease and ulcerative colitis. This review describes the latest advances in understanding functions of SALSA and its different isoforms. Recently recognized functions are related to complement activation and regulation, endothelial development and epithelial homeostasis. In addition, we suggest mechanisms how SALSA regulates inflammation at the mucosal surfaces.

DMBT1 involvement in the human aortic endothelial cell response to Streptococcus mutans

“…In the present study, we demonstrated that HAECs produced and released DMBT1 in response to stimulation with S. mutans. DMBT1 has been shown to be expressed in various epithelial and non-epithelial tissue types (Reichhardt et al, 2017). At mucosal surfaces, DMBT1…”

“…DMBT1 (deleted in malignant brain tumors 1), also known as salivary agglutinin (Ericson & Rundegren, ) or gp‐340 (Holmskov et al, ), belongs to the scavenger receptor cysteine–rich superfamily and is expressed in epithelial and non‐epithelial tissues throughout the body (Osei, Deivanayagam, & Nichols, ; Reichhardt, Holmskov, & Meri, ). DMBT1 exists as two variants, namely, as secretory and cell–associated types, and the secretory type exists in two conformations, namely, in soluble and immobilized forms (Osei et al, ).…”

“…We have also demonstrated that S. mutans upregulates intracellular toll-like receptor 2 (TLR2) and nucleotide-binding oligomerization domain 2 (NOD2) in HAECs and that the cytokine production induced by invasive S. mutans occurs via intracellular TLR2 and NOD2 in HAECs (Nagata & Oho, 2017). DMBT1 (deleted in malignant brain tumors 1), also known as salivary agglutinin (Ericson & Rundegren, 1983) or gp-340 (Holmskov et al, 1997), belongs to the scavenger receptor cysteine-rich superfamily and is expressed in epithelial and non-epithelial tissues throughout the body (Osei, Deivanayagam, & Nichols, 2018;Reichhardt, Holmskov, & Meri, 2017). DMBT1 exists as two variants, namely, as secretory and cell-associated types, and the secretory type exists in two conformations, namely, in soluble and immobilized forms (Osei et al, 2018).…”

The structure of SALSA/DMBT1 SRCR domains reveal the conserved ligand-binding mechanism of the ancient SRCR-fold

“…The Salivary Scavenger and Agglutinin (SALSA), also known as gp340, ‘deleted in malignant brain tumors 1’ (DMBT1) and salivary agglutinin (SAG), is a multifunctional molecule found in high abundance on human mucosal surfaces [1–4]. SALSA has widespread functions in innate immunity, inflammation, epithelial homeostasis and tumour suppression [5–7]. SALSA binds and agglutinates a broad spectrum of pathogens including, but not limited to, human immunodeficiency virus type 1, Helicobacter pylori , Salmonella enterica serovar Typhimurium , and many types of streptococci [8–11].…”

“…The first 13 SRCRs are 109 amino acid (aa) domains found as “pearls on a string” separated by SRCR interspersed domains (SIDs) (Figure 1a) [1, 21]. The SIDs are 20-23 aa long stretches of predicted disorder containing a number of glycosylation sites which have been proposed to force them into an extended conformation of roughly 7 nm [7]. In addition to this main form, alternative splicing and copy number variation mechanisms lead to expression of variants of SALSA containing variable numbers of SRCRs in the N-terminal region.…”