LAPTM4B controls the sphingolipid and ether lipid signature of small extracellular vesicles

Dichlberger, Andrea; Zhou, Kejun; Back, Nathan; Nyholm, Thomas K.M.; Backman, Anders P. E.; Mattjus, Peter; Ikonen, Elina; Blom, Tomas

doi:10.1016/j.bbalip.2020.158855

Cited by 10 publications

(14 citation statements)

References 79 publications

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“…In our study, we first identified that the LAPTM4B gene is related to RCC proliferation and metastasis. This ceramide-interacting protein, across quaternary membranes, can modulate the mTOR signaling pathway associated with autophagy (Dichlberger et al, 2021;Ji et al, 2022); LAPTM4B expression has been shown to be a poor prognostic marker in ovarian cancer (Yin et al, 2011). It would be worth noting that LAPTM4B-35, a protein encoded by LAPTM4B, is highly expressed in various solid tumors (Meng et al, 2016), and its overexpression is associated with poor prognosis in many malignancies, including ovarian, breast, cervical, and prostate cancers (Zhou et al, 2007;Qiao and Hu, 2015).…”

Section: Discussionmentioning

confidence: 99%

Autophagy-related gene LAPTM4B promotes the progression of renal clear cell carcinoma and is associated with immunity

Wang

et al. 2023

Front. Pharmacol.

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Renal cell carcinoma (RCC) is a common urologic disease. Currently, surgery is the primary treatment for renal cancer; immunotherapy is not as effective a treatment strategy as expected. Hence, understanding the mechanism in the tumor immune microenvironment (TME) and exploring novel immunotherapeutic targets are considered important. Recent studies have demonstrated that autophagy could affect the immune environment of renal cell carcinoma and induce proliferation and apoptosis of cancer cells. By comparing lysosomal genes and regulating autophagy genes, we identified the LAPTM4B gene to be related to RCC autophagy. By analyzing the TCGA-KIRC cohort using bioinformatics, we found M2 macrophages associated with tumor metastasis to be significantly increased in the immune microenvironment of patients with high expression of LAPTM4B. GO/KEGG/GSEA/GSVA results showed significant differences in tumor autophagy- and metastasis-related pathways. Single-cell sequencing was used to compare the expression of LAPTM4B in different cell types and obtain the differences in lysosomal and autophagy pathway activities in different ccRCC cells. Subsequently, we confirmed the differential expression of LAPTM4B in renal cell carcinoma of different Fuhrman grades using western blotting. Downregulation of LAPTM4B expression significantly reduced the proliferation of renal cell carcinoma cells and promoted cell apoptosis through cell experiments. Overall, our study demonstrated that the autophagy-related gene LAPTM4B plays a critical role in the TME of RCC, and suggested that LAPTM4B is a potential therapeutic target for RCC immunotherapy.

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Section: Discussionmentioning

confidence: 99%

Autophagy-related gene LAPTM4B promotes the progression of renal clear cell carcinoma and is associated with immunity

Wang

et al. 2023

Front. Pharmacol.

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“…SDC1 regulates CXCL1 expression and trophoblast invasion into the endometrium during the peri-implantation period [ 44 ]. As a member of the lysosomal-associated protein transmembrane (LAPTM) family, LAPTM4B affect membrane properties of EVs by regulating lipid composition [ 45 ]. Based on the above-described results of the current study and other studies, we suggest that sperm-borne miR-34c may be involved in the development of implantation-competent blastocysts.…”

Section: Discussionmentioning

confidence: 99%

Sperm-borne microRNA-34c regulates maternal mRNA degradation and preimplantation embryonic development in mice

Cui

Zhuang

et al. 2023

Reprod Biol Endocrinol

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Background Studies have shown that sperm-borne microRNAs (miRNAs) are involved in mammalian preimplantation embryonic development. In humans, spermatozoan miR-34c levels are correlated with in vitro fertilization outcomes, such as embryo quality and the clinical pregnancy and live birth rates. In rabbits and cows, miR-34c improves the developmental competence of embryos generated by somatic cell nuclear transfer. However, the mechanisms underlying the regulation of embryonic development by miR-34c remain unknown. Methods Female C57BL/6 mice (6–8 weeks old) were superovulated, and pronucleated zygotes were collected and microinjected with an miR-34c inhibitor or a negative-control RNA. The embryonic development of the microinjected zygotes was evaluated, and the messenger RNA (mRNA) expression profiles of the embryos at the two-cell, four-cell and blastocyst stages (five embryos per group) were determined by RNA sequencing analysis. Gene expression levels were verified by reverse transcription–quantitative polymerase chain reaction. Cluster analysis and heat map visualization were performed to detect differentially expressed mRNAs. Pathway and process enrichment analyses were performed using ontology resources. Differentially expressed mRNAs were systematically analyzed using the Search Tool for the Retrieval of Interacting Genes/Proteins database to determine their biological functions. Results Embryonic developmental potential was significantly reduced in zygotes microinjected with the miR-34c inhibitor compared with those microinjected with a negative-control RNA. Two-cell stage embryos microinjected with an miR-34c inhibitor presented altered transcriptomic profiles, with upregulated expression of maternal miR-34c target mRNAs and classical maternal mRNAs. Differentially expressed transcripts were mainly of genes associated with lipid metabolism and cellular membrane function at the two-cell stage, with cell-cycle phase transition and energy metabolism at the four-cell stage; and with vesicle organization, lipid biosynthetic process and endomembrane system organization at the blastocyst stage. We also showed that genes related to preimplantation embryonic development, including Alkbh4, Sp1, Mapk14, Sin3a, Sdc1 and Laptm4b, were significantly downregulated after microinjection of an miR-34c inhibitor. Conclusions Sperm-borne miR-34c may regulate preimplantation embryonic development by affecting multiple biological processes, such as maternal mRNA degradation, cellular metabolism, cell proliferation and blastocyst implantation. Our data demonstrate the importance of sperm-derived miRNAs in the development of preimplantation embryos.

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“…However, ceramide levels in EVs are highly important in disease condition (Elsherbini & Bieberich, 2018). Recently, Dichlberger et al., found that the ceramide interacting protein, lysosome‐associated protein transmembrane 4B (LAPTM4B), regulates the glycosphingolipid composition of small EVs (Dichlberger et al., 2021). Interestingly, LAPTM4B deficiency increased glycosphingolipids in the EVs, leaving ceramide unaffected even though LAPTM4B regulates the subcellular distribution of ceramide (Dichlberger et al., 2021).…”

Section: Discussionmentioning

confidence: 99%

“…Recently, Dichlberger et al., found that the ceramide interacting protein, lysosome‐associated protein transmembrane 4B (LAPTM4B), regulates the glycosphingolipid composition of small EVs (Dichlberger et al., 2021). Interestingly, LAPTM4B deficiency increased glycosphingolipids in the EVs, leaving ceramide unaffected even though LAPTM4B regulates the subcellular distribution of ceramide (Dichlberger et al., 2021). In our study, when the ceramide transporter function of CERT was inhibited with HPA‐12, not only EVs were decreased in numbers, but also in their content of ceramide, SM, sphingosine and sphinganine, while glycosphingolipids were poorly affected.…”

Section: Discussionmentioning

confidence: 99%

Function of ceramide transfer protein for biogenesis and sphingolipid composition of extracellular vesicles

Crivelli

Giovagnoni

Zhu

et al. 2022

J of Extracellular Vesicle

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The formation of extracellular vesicles (EVs) is induced by the sphingolipid ceramide. How this pathway is regulated is not entirely understood. Here, we report that the ceramide transport protein (CERT) mediates a non‐vesicular transport of ceramide between the endoplasmic reticulum (ER) and the multivesicular endosome at contact sites. The process depends on the interaction of CERT's PH domain with PI4P generated by PI4KIIα at endosomes. Furthermore, a complex is formed between the START domain of CERT, which carries ceramide, and the Tsg101 protein, which is part of the endosomal sorting complex required for transport (ESCRT‐I). Inhibition of ceramide biosynthesis reduces CERT‐Tsg101 complex formation. Overexpression of CERT increases EV secretion while its inhibition reduces EV formation and the concentration of ceramides and sphingomyelins in EVs. In conclusion, we discovered a function of CERT in regulating the sphingolipid composition and biogenesis of EVs, which links ceramide to the ESCRT‐dependent pathway.

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LAPTM4B controls the sphingolipid and ether lipid signature of small extracellular vesicles

Cited by 10 publications

References 79 publications

Autophagy-related gene LAPTM4B promotes the progression of renal clear cell carcinoma and is associated with immunity

Autophagy-related gene LAPTM4B promotes the progression of renal clear cell carcinoma and is associated with immunity

Sperm-borne microRNA-34c regulates maternal mRNA degradation and preimplantation embryonic development in mice

Function of ceramide transfer protein for biogenesis and sphingolipid composition of extracellular vesicles

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