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Secretory Sphingomyelinase in Health and Disease

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Secretory Sphingomyelinase in Health and Disease Biol. Chem. 2015; 396(6-7): 707–736 Review Open Access Johannes Kornhuber*, Cosima Rhein, Christian P. Müller and Christiane Mühle Secretory sphingomyelinase in health and disease Abstract: Acid sphingomyelinase (ASM), a key enzyme may be both a promising clinical chemistry marker and a in sphingolipid metabolism, hydrolyzes sphingomy- therapeutic target. elin to ceramide and phosphorylcholine. In mammals, the expression of a single gene, SMPD1, results in two Keywords: ceramide; inflammation; lipids; secretory forms of the enzyme that differ in several characteristics. sphingomyelinase; sphingomyelin; sphingomyelinase. Lysosomal ASM (L-ASM) is located within the lysosome, 2+ requires no additional Zn ions for activation and is gly- DOI 10.1515/hsz-2015-0109 cosylated mainly with high-mannose oligosaccharides. Received January 20, 2015; accepted February 16, 2015; previously By contrast, the secretory ASM (S-ASM) is located extra- published online March 24, 2015 cellularly, requires Zn2+ ions for activation, has a complex glycosylation pattern and has a longer in vivo half-life. In this review, we summarize current knowledge regarding the physiology and pathophysiology of S-ASM, includ- Introduction ing its sources and distribution, molecular and cellular Acid sphingomyelinase (ASM, EC 3.1.4.12) plays a major mechanisms of generation and regulation and relevant role in sphingolipid metabolism because it catalyzes the in vitro and in vivo studies. Polymorphisms or mutations hydrolysis of sphingomyelin (SM) to ceramide and phos- of SMPD1 lead to decreased S-ASM activity, as detected in phorylcholine. Ceramide and related products, such as patients with Niemann-Pick disease B. Thus, lower serum/ spingosine-1-phosphate, are important lipid signaling plasma activities of S-ASM are trait markers. No genetic molecules. These molecules are involved in a variety of causes of increased S-ASM activity have been identified. molecular and cellular processes and play a central role Instead, elevated activity is the result of enhanced release in a growing number of human diseases. The multiple (e.g., induced by lipopolysaccharide and cytokine stimu- physiological sources of ceramide in mammalian cells lation) or increased enzyme activation (e.g., induced by (de novo synthesis from palmitoyl-CoA and serine, syn- oxidative stress). Increased S-ASM activity in serum or thesis from sphingosine and fatty acid, SM catabolism, plasma is a state marker of a wide range of diseases. In hydrolysis of glycosylceramide and galactosylceramide, particular, high S-ASM activity occurs in inflammation of dephosphorylation of ceramide-1-phosphate) do not con- the endothelium and liver. Several studies have demon- tribute equally to the pool, but the degradation of SM by strated a correlation between S-ASM activity and mortality the ASM is an important source of ceramide. The promi- induced by severe inflammatory diseases. Serial measure- nent position of sphingomyelinases is mainly attributed ments of S-ASM reveal prolonged activation and, there- to the abundance of their substrate SM in cell membranes fore, the measurement of this enzyme may also provide (van Meer et al., 2008). Because of its spatially bulky head information on past inflammatory processes. Thus, S-ASM group, SM is restricted to the membrane leaflet where it is generated, i.e., the luminal Golgi leaflet or – after vesicu- lar transport – the outer leaflet of the plasma membrane *Corresponding author: Johannes Kornhuber, Department of (Gault et al., 2010), unless flipping is aided by a specific Psychiatry and Psychotherapy, Friedrich Alexander University of flippase (Sharom, 2011). However, of the known flip- Erlangen-Nürnberg (FAU), Schwabachanlage 6, D-91054 Erlangen, pases, none is active toward SM (Takatsu et al., 2014). Germany, e-mail: [email protected] Mammalian cells contain a single gene for ASM (SMPD1), Cosima Rhein, Christian P. Müller and Christiane Mühle: Department of Psychiatry and Psychotherapy, Friedrich Alexander which is responsible for the generation of both the secre- University of Erlangen-Nürnberg (FAU), Schwabachanlage 6, tory (S-ASM) and lysosomal (L-ASM) forms (Schissel D-91054 Erlangen, Germany et al., 1996a). S- and L-ASM originate from the same gene ©2015, Johannes Kornhuber et al., published by De Gruyter. This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License. 708 J. Kornhuber et al.: Secretory sphingomyelinase without the involvement of alternative RNA splicing as lability at 55°C (Spence et al., 1979) and exceptionally they can be produced from the same full-length cDNA longer half-life (Jenkins et al., 2010), different molecular (Schissel et al., 1998b). The common mRNA is also trans- weight of the protein core due to an intact C-terminus lated in the same reading frame because the resulting (Jenkins et al., 2011b) and different N-terminal proteolytic L- and S-ASM proteins are similar in size and are both rec- processing. In addition, S-ASM has a complex N-glyco- ognized by antibodies prepared against L-ASM (Schissel sylation pattern (Ferlinz et al., 1994; Hurwitz et al., 1994b) et al., 1996a, 1998b). By contrast, in the nematode Cae- that enables resistance to endoglycosidase H and results norhabditis elegans, three genes have been identified (Lin in a different localization (Schissel et al., 1998b) com- et al., 1998; Kim and Sun, 2012) on different chromosomes pared to L-ASM with high-mannose oligosaccharides for (Yook et al., 2012): the product of asm-1 is almost entirely lysosomal targeting (Kornfeld, 1987). Whether L-ASM and secreted but is Zn2+-independent, whereas only 20% of S-ASM act on different SM pools in the cell, which would the asm-2 product is secreted and requires Zn2+. The asm-3 result in distinct effects via differential ceramide genera- protein with the strongest homology to human ASM and tion, remains unclear (Jenkins et al., 2010). sensitivity to desipramine and clomipramine (Lin et al., 1998; Kim and Sun, 2012) may correspond to L-ASM. The presence of separate genes for the secreted sphingomyeli- Genetic impact on S-ASM activity nase in C. elegans with developmentally regulated expres- sion emphasizes the critical importance of the secreted A number of genetic sequence variations and mutations enzyme. However, in mammalian organisms the role, influence S-ASM activity and the process of generating L- function and regulation of S-ASM are not as well under- or S-ASM. The repeat number variation of a hexanucleo- stood as those of L-ASM. Several previous reviews cover tide sequence – c.108GCTGGC(3_8)/p.37LA(3)_8) – that various aspects of S-ASM physiology and pathophysiology leads to the modification of the signal peptide of the pre- (Tabas, 1999; Goni and Alonso, 2002; Smith and Schuch- pro-form of ASM (Wan and Schuchman, 1995), was associ- man, 2008; Jenkins et al., 2009; Pavoine and Pecker, 2009; ated with S-ASM activity but not L-ASM activity in a cell He and Schuchman, 2012). In this review, we focus on the culture model. In addition, analysis of a human sample progress made in recent years specifically on mamma- resulted in a significant association of S-ASM activity lian S-ASM and some aspects of secreted L-ASM, and we with the number of hexanucleotide repeats; levels were examine novel studies investigating S-ASM as a mediator highest in subjects homozygous for six repeats, inter- of pathogenic processes, a potential therapeutic target and mediate in subjects homozygous for five repeats, and a biomarker in human diseases. The sequence numbering lowest in subjects homozygous for four repeats. One of at the DNA and protein level in this review is based on the the most frequent SMPD1 sequence variations, rs1050239/ standard database reference sequence NM_000543.4 with c.1522G > A/p.G508R (Rhein et al., 2014), has been associ- 631 amino acids, which leads to a shift of +2 amino acids ated with S-ASM activity but not L-ASM activity. S-ASM when referring to some published positions because of activity was measured in the blood plasma of healthy an additional leucine-alanine dipeptide within the poly- young adults and was highest in subjects homozygous morphic signal peptide. for the major G allele, intermediate in heterozygous sub- jects and lowest in subjects homozygous for the A allele (Reichel et al., 2014). Importantly, the influences of these two polymorphic sites on S-ASM activity are independ- Molecular and cellular regulatory ent (Rhein et al., 2014). The nonsynonymous variation mechanisms of S-ASM activity rs141641266/c.1460C > T/p.A487V, previously assumed to be a missense mutation causing Niemann-Pick disease Two distinct enzymes arise from the single SMPD1 gene (NPD) type B (Simonaro et al., 2002), leads to normal because of differential modification and trafficking pro- L-ASM and only slightly lower S-ASM activity levels (Rhein cesses. The lysosomal form (L-ASM) is located in the et al., 2013). endolysosomal compartment, whereas the secretory form More than 100 clinically relevant missense mutations (S-ASM) is released by the secretory pathway (Schissel in the SMPD1 gene leading to enzymes with decreased cat- et al., 1996a; Jenkins et al., 2010). S-ASM differs from the alytic activity, the cause of autosomal recessive NPD types lysosomal form by its dependence on exogenously added A and B (Brady et al., 1966; Schuchman, 2010), have been Zn2+ ions (Schissel et al., 1998b) associated with its inhi- deposited in the Human Gene Mutation Database (www. bition by ethylenediaminetetraacetic acid (EDTA), heat hgmd.cf.ac.uk). While genotype/phenotype correlations J. Kornhuber et al.: Secretory sphingomyelinase 709 are typically complex, the DR608 deletion mutation how S-ASM activity is influenced by alternative splicing appears to protect patients against the development of has not been investigated. The unexpectedly mild NPD-B the more severe neuropathic NPD form type A (Schuch- phenotype and 20–25% residual L-ASM activity observed man and Miranda, 1997).
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