Secretion of Acid Sphingomyelinase is Affected by its Polymorphic Signal Peptide

Abstract

Background: Acid sphingomyelinase (ASM) catalyses the hydrolysis of sphingomyelin into ceramide, which acts as a lipid messenger that regulates important cellular functions. Deregulated ASM activity has been reported for different common diseases, but the mechanisms regulating ASM activity are still debated. ASM contains an exceptional signal peptide which is polymorphic due to a variable number of a hexanucleotide sequence that determines the length of the hydrophobic core. We investigated the impact of the signal peptide polymorphism on the regulation of ASM activity and secretion in vivo and in vitro. Methods and Results: Subjects homozygous for the rare 4-repeat allele displayed significantly lower secreted ASM activity than subjects homozygous for the common 6-repeat allele. In vitro, overexpression of ASM variants encoded by 2, 8 or 9 repeats resulted in a significantly lowered ASM secretion rate. Treatment of ASM-overexpressing cells with tumour necrosis factor α induced secretion of ASM, and the secretion rate was highest for the most common ASM variant encoding 6 repeats compared to other naturally occurring variants. Conclusion: We provide evidence that the polymorphic ASM signal peptide regulates ASM secretion. It might be an evolutionary mechanism to increase ASM secretion potential, whereas an increase in lysosomal ASM activity is limited due to deleterious cellular effects.

Alleged Detrimental Mutations in the SMPD1 Gene in Patients with Niemann-Pick Disease

“…The functional relevance of c.107T>C was analyzed together with that of the adjacent polymorphic hexanucleotide repeat. While we obtained data showing that less repeats of the hexanucleotide motif are associated with slightly decreased S-ASM activity in vivo and in vitro [ 8 ], we did not observe a significant reduction of ASM activity associated with c.107T>C, neither in vivo nor in vitro ( Figure 1 ). In contrast, transient transfection of a c.973G-construct into HeLa and MDCK cells did not increase ASM activity compared to control cells, thus confirming that c.973C>G is a NPD mutation ( Figure 1 ).…”

Peripheral Acid Sphingomyelinase Activity Is Associated with Biomarkers and Phenotypes of Alcohol Use and Dependence in Patients and Healthy Controls

“…Genetically determined ASM activity is already known to influence the susceptibility for common human diseases, such as allergy [42]. However, because known single nucleotide polymorphisms or variations in the repeat number within the special signal peptide negatively affect ASM activity [12,43,44], it is rather unlikely that a frequent, but so far undetected, variant within the SMPD1 gene would predispose carriers to developing alcohol dependence, and be the cause of higher S-ASM levels. On the other hand, processes associated with posttranslational modifications, and regulation that modulate ASM trafficking, maturation, or secretion [45], as well as those leading to degradation of the enzyme, could permanently or temporarily be altered in patients.…”

Keep Your Friends Close, but Your Enemies Closer: Role of Acid Sphingomyelinase During Infection and Host Response

“…There are a small number of reports on polymorphisms of the SMPD1 gene locus: V36A, A487V, and G508R as well as hexanucleotide repeat in the signaling peptide (123)(124)(125)(126)(127). In contrast to the variety of missense mutations, there is only a minor effect of these sequence variations on overall activity and function of the enzyme, but they might increase the susceptibility for common diseases such as allergy (125).…”