Sphingomyelin phosphodiesterase 4 (SMPD4)

Sphingomyelin phosphodiesterase 4 (SMPD4), also known as neutral sphingomyelinase 3 (nSMase-3), is an enzyme that hydrolyzes sphingomyelin to produce ceramide and phosphorylcholine at neutral pH[1][2]. SMPD4 is predominantly localized to the endoplasmic reticulum and the nuclear envelope, with key roles in regulating nuclear envelope dynamics, nuclear pore assembly, and centrosome-associated processes during the cell cycle[1][2]. Mutations in SMPD4 result in severe neurodevelopmental disorders characterized by microcephaly and, in surviving individuals, early-onset insulin-dependent diabetes[1][2]. SMPD4’s enzymatic function is critical for maintaining local ceramide balance at the nuclear envelope and centrosome, influencing processes such as neural progenitor proliferation and primary ciliogenesis. Although its catalytic activity contributes little to global sphingolipid pools, it is essential for membrane remodeling events in specific subcellular compartments[1][2]. Currently, there are no clinically established drugs targeting SMPD4, but it remains of high research interest for its roles in neural development and metabolic disease.

Other names

Sphingomyelin phosphodiesterase 4SMPD4KIAA1418SKNYnSMase-3nSMase3FLJ20297FLJ20756NSMASE3NET13Neutral sphingomyelinase 3Neutral sphingomyelinase IIIneutral sphingomyelinase-3NSMASE-3NEDMABANEDMEBAsphingomyelin phosphodiesterase 4neutral membrane (neutral sphingomyelinase-3)

Hydrolysis of sphingomyelin to ceramide and phosphorylcholine (endogenous); for potential drugs, inhibition or activation of sphingomyelinase activity; TNFα can induce SMPD4 enzymatic activity in some cellular contexts