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Sphingolipid de novo biosynthesis is essential for intestine cell survival and barrier function.

ABSTRACT: Serine palmitoyltransferase (SPT) is the rate-limiting enzyme for sphingolipid biosynthesis. SPT has two major subunits, SPTLC1 and SPTLC2. We previously found that liver Sptlc2 deficiency in early life impairs the development of adherens junctions. Here, we investigated the role of Sptlc2 deficiency in intestine. We treated Sptlc2-Flox/villin-Cre-ERT2 mice with tamoxifen (days 1, 2, and 3) to ablate Sptlc2 specifically in the intestine. At day 6 after tamoxifen treatment, Sptlc2-deficient mice had significantly decreased body weight with concurrent diarrhea and rectal bleeding. The number of goblet cells was reduced in both large and small intestine of Sptlc2-deficient mice compared with controls. Sptlc2 deficiency suppressed the level of mucin2 in the colon and increased circulating lipopolysaccharides, suggesting that SPT activity has a housekeeping function in the intestine. All Sptlc2-deficient mice died 7-10 days after tamoxifen treatment. Notably, supplementation with antibiotics and dexamethasone reduced lethality by 70%. We also found that colon specimens from patients with inflammatory bowel diseases had significantly reduced Sptlc2 expression, SPTLC2 staining, and goblet cell numbers. SPT activity is crucial for intestinal cell survival and barrier function.

SUBMITTER: Li Z

PROVIDER: S-EPMC5833386 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Sphingolipid de novo biosynthesis is essential for intestine cell survival and barrier function.

Li Zhiqiang Z Kabir Inamul I Tietelman Gladys G Huan Chongmin C Fan Jianglin J Worgall Tilla T Jiang Xian-Cheng XC

Cell death & disease 20180207 2

Serine palmitoyltransferase (SPT) is the rate-limiting enzyme for sphingolipid biosynthesis. SPT has two major subunits, SPTLC1 and SPTLC2. We previously found that liver Sptlc2 deficiency in early life impairs the development of adherens junctions. Here, we investigated the role of Sptlc2 deficiency in intestine. We treated Sptlc2-Flox/villin-Cre-ER<sup>T2</sup> mice with tamoxifen (days 1, 2, and 3) to ablate Sptlc2 specifically in the intestine. At day 6 after tamoxifen treatment, Sptlc2-defi ...[more]

PMID: 29415989

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Project description:The yeast-to-hypha transition is a key virulence attribute of the opportunistic human fungal pathogen Candida albicans, since it is closely tied to infection-associated processes such as tissue invasion and escape from phagocytes. While the nature of hypha-associated gene expression required for fungal virulence has been thoroughly investigated, potential morphotype-dependent activity of metabolic pathways remained unclear. Here, we combined global transcriptome and metabolome analyses for the wild-type SC5314 and the hypha-defective hgc1Δ and cph1Δefg1Δ strains under three hypha-inducing (human serum, N-acetylglucosamine, and alkaline pH) and two yeast-promoting conditions to identify metabolic adaptions that accompany the filamentation process. We identified morphotype-related activities of distinct pathways and a metabolic core signature of 26 metabolites with consistent depletion or enrichment during the yeast-to-hypha transition. Most strikingly, we found a hypha-associated activation of de novo sphingolipid biosynthesis, indicating a connection of this pathway and filamentous growth. Consequently, pharmacological inhibition of this partially fungus-specific pathway resulted in strongly impaired filamentation, verifying the necessity of de novo sphingolipid biosynthesis for proper hypha formation. IMPORTANCE The reversible switch of Candida albicans between unicellular yeast and multicellular hyphal growth is accompanied by a well-studied hypha-associated gene expression, encoding virulence factors like adhesins, toxins, or nutrient scavengers. The investigation of this gene expression consequently led to fundamental insights into the pathogenesis of this fungus. In this study, we applied this concept to hypha-associated metabolic adaptations and identified morphotype-dependent activities of distinct pathways and a stimulus-independent metabolic signature of hyphae. Most strikingly, we found the induction of de novo sphingolipid biosynthesis as hypha associated and essential for the filamentation of C. albicans. These findings verified the presence of morphotype-specific metabolic traits in the fungus, which appear connected to the fungal virulence. Furthermore, the here-provided comprehensive description of the fungal metabolome will help to foster future research and lead to a better understanding of fungal physiology.

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Sphingolipid de novo biosynthesis is essential for intestine cell survival and barrier function.

Publications

Sphingolipid de novo biosynthesis is essential for intestine cell survival and barrier function.

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