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ALKALINE CERAMIDASE 1; ACER1

ALKALINE CERAMIDASE 1; ACER1

Alternative titles; symbolsALKALINE CDase 1ALKCDase1HGNC Approved Gene Symbol: ACER1Cytogenetic location: 19p13.3 Genomic coordinates (GRCh38): 19:6,306,141-...

Alternative titles; symbols

  • ALKALINE CDase 1
  • ALKCDase1

HGNC Approved Gene Symbol: ACER1

Cytogenetic location: 19p13.3 Genomic coordinates (GRCh38): 19:6,306,141-6,360,367 (from NCBI)

▼ Description
Ceramides are synthesized during epidermal differentiation and accumulate within the interstices of the stratum corneum, where they represent critical components of the epidermal permeability barrier. Excess cellular ceramide can trigger antimitogenic signals and induce apoptosis, and the ceramide metabolites sphingosine and sphingosine-1-phosphate (S1P) are important bioregulatory molecules. Ceramide hydrolysis in the nucleated cell layers regulates keratinocyte proliferation and apoptosis in response to external stress. Ceramide hydrolysis also occurs at the stratum corneum, releasing free sphingoid base that functions as an endogenous antimicrobial agent. ACER1 is highly expressed in epidermis and catalyzes the hydrolysis of very long chain ceramides to generate sphingosine (Houben et al., 2006; Sun et al., 2008).

▼ Cloning and Expression
Mao et al. (2003) cloned mouse Acer1. The deduced 270-amino acid protein has 4 transmembrane domains and a C-terminal Golgi-endoplasmic reticulum (ER) retrieval signal. RT-PCR of mouse tissues detected high Acer1 expression in skin, with very low expression in all other tissues examined. Epitope-tagged Acer1 expressed in HeLa cells localized in a perinuclear reticulum network that overlapped with an ER marker.

Using quantitative RT-PCR, Houben et al. (2006) found that human ACER1, which they called ALKCDase1, was highly expressed in whole human epidermis, with much lower expression in kidney, trachea, and thymus. Expression of ALCDase1 was low in undifferentiated cultured human keratinocytes and increased with differentiation. In situ hybridization detected ALKCDase1 expression in the outer epidermis, but not in the basal cell layer.

By searching an EST database for sequences similar to mouse Acer1, followed by 5-prime RACE and PCR of a neonatal skin keratinocyte cDNA library, Sun et al. (2008) cloned full-length human ACER1. The deduced 264-amino acid protein shares 88% identity with mouse Acer1. Northern blot analysis detected a 1.5-kb transcript that was highly expressed in skin, with little to no expression in other tissues examined. Semiquantitative RT-PCR detected high expression in human epidermal keratinocytes, but not in dermal fibroblasts, the immortalized keratinocyte cell line HaCaT, or the epidermoid carcinoma cell line A431. Transfection of ACER1 into HaCaT cells resulted in ACER1 expression in a perinuclear distribution that overlapped with an ER marker.

▼ Gene Function
By assaying microsomes prepared from transfected yeast and mammalian cells, Mao et al. (2003) found that mouse Acer1 showed strict specificity for D-erythro-ceramide. Acer1 had an alkaline pH optimum of 8.0. It was slightly activated by Ca(2+) and was inhibited by other divalent cations and by its product, sphingosine. Overexpression of Acer1 in HeLa cells reduced the incorporation of radiolabeled dihydrosphingosine into ceramide and complex sphingolipids and increased the content of radiolabeled S1P. Thin layer chromatography revealed that overexpression of Acer1 selectively lowered the cellular levels of D-erythro-C(24:1)-ceramide, but not other ceramide species. Mao et al. (2003) concluded that ACER1 has a role in regulating the levels of the bioactive lipids ceramide and S1P, as well as complex sphingolipids.

By assaying the microsomal fraction of yeast expressing human ACER1, Sun et al. (2008) showed that ACER1 exhibited high ceramidase activity toward the very long chain erythroceramide D-erythro-C(24:1)-ceramide and lower activity toward D-erythro-C(24:0)-ceramide and D-erythro-C(18)-ceramide. It showed no activity against erythroceramides with shorter chain lengths or against dihydroceramides and phytoceramides. ACER1 had a pH optimum of about 8 and was stimulated by calcium. EGF (131530) exposure downregulated ACER1 mRNA and inhibited calcium-induced upregulation of ACER1 mRNA. Overexpression of ACER1 in epidermal keratinocytes reduced the levels of very long chain erythroceramides, particularly those containing very long chain unsaturated fatty acids, and increased the levels of sphingosine, S1P, and ceramides containing medium or long chain fatty acids. Knockdown of ACER1 expression via small interfering RNA in epidermal keratinocytes inhibited calcium-induced generation of sphingosine and S1P, but not ceramides, and attenuated calcium-induced growth arrest and differentiation.

▼ Mapping
Hartz (2010) mapped the ACER1 gene to chromosome 19p13.3 based on an alignment of the ACER1 sequence (GenBank AF347024) with the genomic sequence (GRCh37).

Tags: 19p13.3