Abstract
Catalytically defective rare variants of Sialic acid Acetyl Esterase (SIAE) have previously been linked to autoimmunity. Studies presented here confirm that the M89V SIAE protein and all other products of common variant alleles of SIAE are catalytically normal. Although overexpressing transfected non-lymphoid cells secrete small amounts of SIAE that can associate with the cell surface, normal human lymphocytes do not exhibit cell surface SIAE, supporting genetic evidence in mice that indicates that this protein functions in a lymphocyte intrinsic manner. Analyses of the plasma proteome also indicate that SIAE is not secreted in vivo. A re-analysis exclusively of catalytically defective rare variant alleles of SIAE in subjects in which this gene was completely sequenced confirmed an association of SIAE with autoimmunity. A subset of catalytically defective rare variant SIAE alleles has previously been typed in a large genotyping study comparing a diverse group of disease subjects and controls; our re-analysis of this data shows that catalytically defective alleles are enriched in disease subjects. These data suggest that SIAE may be associated with autoimmunity and that further study of catalytically defective rare variant SIAE alleles in terms of autoimmune disease susceptibility is strongly warranted.
Highlights
Sialic acid acetyl esterase (SIAE) removes acetyl moieties from the 9-OH position of sialic acid, and permits a2,6 linked sialic acid on N-glycans on B cell glycoproteins to interact with CD22/ Siglec-2, a sialic acid binding lectin that can inhibit B cell antigen receptor signaling [1,2,3]
Functional studies on all identified rare variants will most accurately identify those that should be considered relevant to quantify in disease subjects and controls
A very small fraction of overexpressed wild type SIAE is secreted as revealed in pulse-chase studies, and this minimal secretion observed is an in vitro phenomenon of no proven physiological significance
Summary
Sialic acid acetyl esterase (SIAE) removes acetyl moieties from the 9-OH position of sialic acid, and permits a2,6 linked sialic acid on N-glycans on B cell glycoproteins to interact with CD22/ Siglec-2, a sialic acid binding lectin that can inhibit B cell antigen receptor signaling [1,2,3]. We showed in overexpression studies that SIAE can be secreted and decorate the surface of over-expressing transfected nonlymphoid cells presumably by binding to some extracellular component but the physiological relevance of secretion and cell surface expression of this protein was not critically evaluated by in vivo studies [1]. This protein must function in a post Golgi compartment since a2–6 linked sialic acids moieties are added and acetylated in the 9-OH position in the trans-Golgi. SIAE is expressed in many different tissues, this result indirectly argued against an in vivo role for secreted SIAE
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