LAPTM4B facilitates late endosomal ceramide export to control cell death pathways

Blom, Tomas; Li, Shiqian; Dichlberger, Andrea; Back, Nathan; Kim, Young Ah; Loizides‐Mangold, Ursula; Riezman, Howard; Bittman, Robert; Ikonen, Elina

doi:10.1038/nchembio.1889

Cited by 53 publications

(70 citation statements)

References 50 publications

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“…One conventional immune modulatory therapies in sarcoidosis is Chloroquine 42 which has been shown to inhibit lysosomal function and modulates autophagy 43 . Surprisingly, the LAPTM4B gene, which is involved in lysosomal machinery and has been shown to interact with ceramide to facilitate its removal from the late endosomal organelles was downregulated 44 (Fig. 4).…”

Section: Discussionmentioning

confidence: 99%

RNA-sequencing Identifies Novel Pathways in Sarcoidosis Monocytes

Talreja

Farshi

Alazizi

et al. 2017

Sci Rep

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Sarcoidosis is a complex systemic granulomatous disorder of unknown etiology. Genome-wide association studies have not been able to explain a causative role for nucleotide variation in its pathogenesis. The goal of the present study was to identify the gene expression profile and the cellular pathways altered in sarcoidosis monocytes via RNA-sequencing. Peripheral blood monocytes play a role in sarcoidosis inflammation. Therefore, we determined and compared the transcriptional signature of monocytes from peripheral blood from sarcoidosis patients and healthy controls via RNA-sequencing. We found 2,446 differentially expressed (DE) genes between sarcoidosis and healthy control monocytes. Analysis of these DE genes showed enrichment for ribosome, phagocytosis, lysosome, proteasome, oxidative phosphorylation and metabolic pathways. RNA-sequencing identified upregulation of genes involved in phagocytosis and lysosomal pathway in sarcoidosis monocytes, whereas genes involved in proteasome degradation and ribosomal pathways were downregulated. Further studies are needed to investigate the role of specific genes involved in the identified pathways and their possible interaction leading to sarcoidosis pathology.

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Section: Discussionmentioning

confidence: 99%

RNA-sequencing Identifies Novel Pathways in Sarcoidosis Monocytes

Talreja

Farshi

Alazizi

et al. 2017

Sci Rep

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“…NSMase-dependent sphingolipid metabolism promoted MOMP via coordinated activation of BAX and BAK, suggesting that BCL-2 homology 3 (BH3)-only proteins and the specific sphingolipid milieu at the mitochondrial membrane regulate apoptosis 88 . Moreover, silencing of the gene encoding lysosomal-associated transmembrane protein 4B (LAPTM4B) — which facilitates removal of ceramide from late endosomal (LE) organelles — induced sphingolipid accumulation in LE organelles, destabilized the lysosomal membrane and resulted in resistance to caspase 3 activation and apoptosis induced by chemotherapeutic drugs in A431 human epidermoid carcinoma cells 89 (FIG. 2).…”

Section: Sphingolipids In Cancer Cell Deathmentioning

confidence: 99%

“…Since then, there have been myriad studies showing that endogenously generated ceramide is a bona fide inducer of apoptosis that is regulated by various mechanisms in a cell-type-dependent and/or context-dependent manner (as discussed in the main text) 36,37,86,89 . However, there are also studies that have demonstrated that induction of ceramide might protect some cancer cells from cell death.…”

Section: Sphingolipids In Cancer Cell Deathmentioning

confidence: 99%

“…Ceramide accumulation in the mitochondrial membrane induces BAX recruitment to the mitochondria, resulting in mitochondrial outer membrane permeabilization (MOMP), caspase activation and apoptosis in response to radiation 86–88 . In addition, regulation of ceramide transport from late endosomal organelles by lysosomal-associated transmembrane protein 4B (LAPTM4B) stabilizes lysosomal membranes, leading to ceramide-mediated caspase 3 activation and apoptosis induced by chemotherapeutic drugs 89 . Activation of serine/ threonine-protein phosphatase 2A (PP2A) is mediated by direct binding between phosphatase 2A inhibitor I2PP2A and ceramide or FTY720, a sphingosine analogue drug, leading to receptor-interacting serine/threonine-protein kinase 1 (RIPK1)-dependent necroptosis in lung cancer cells 91 .…”

Section: Figurementioning

confidence: 99%

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Sphingolipid metabolism in cancer signalling and therapy

2017

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Sphingolipids, including the two central bioactive lipids ceramide and sphingosine-1-phosphate (S1P), have opposing roles in regulating cancer cell death and survival, respectively, and there have been exciting developments in understanding how sphingolipid metabolism and signalling regulate these processes in response to anticancer therapy. Recent studies have provided mechanistic details of the roles of sphingolipids and their downstream targets in the regulation of tumour growth and response to chemotherapy, radiotherapy and/or immunotherapy using innovative molecular, genetic and pharmacological tools to target sphingolipid signalling nodes in cancer cells. For example, structure–function-based studies have provided innovative opportunities to develop mechanism-based anticancer therapeutic strategies to restore anti-proliferative ceramide signalling and/or inhibit pro-survival S1P–S1P receptor (S1PR) signalling. This Review summarizes how ceramide-induced cellular stress mediates cancer cell death through various mechanisms involving the induction of apoptosis, necroptosis and/or mitophagy. Moreover, the metabolism of ceramide for S1P biosynthesis, which is mediated by sphingosine kinase 1 and 2, and its role in influencing cancer cell growth, drug resistance and tumour metastasis through S1PR-dependent or receptor-independent signalling are highlighted. Finally, studies targeting enzymes involved in sphingolipid metabolism and/or signalling and their clinical implications for improving cancer therapeutics are also presented.

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“…On the other hand, cells with low LAPTM4B expression made ceramide sequestered in late endosome, protecting cells from ceramide toxicity in the late endosome but sensitizing cells to lysosome-mediated death. 52 …”

Section: Functions Of Laptm4b and The Mechanisms Thereofmentioning

confidence: 99%

LAPTM4B: an oncogene in various solid tumors and its functions

Zhang

Wang

et al. 2016

Oncogene

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The oncogene Lysosome-associated protein transmembrane-4β (LAPTM4B) gene was identified, and the polymorphism region in the 5′-UTR of this gene was certified to be associated with tumor susceptibility. LAPTM4B-35 protein was found to be highly expressed in various solid tumors and could be a poor prognosis marker. The functions of LAPTM4B in solid tumors were also explored. It is suggested that LAPTM4B could promote the proliferation of tumor cells, boost invasion and metastasis, resist apoptosis, initiate autophagy and assist drug resistance.

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LAPTM4B facilitates late endosomal ceramide export to control cell death pathways

Cited by 53 publications

References 50 publications

RNA-sequencing Identifies Novel Pathways in Sarcoidosis Monocytes

RNA-sequencing Identifies Novel Pathways in Sarcoidosis Monocytes

Sphingolipid metabolism in cancer signalling and therapy

LAPTM4B: an oncogene in various solid tumors and its functions

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