The small GTPase RAB10 regulates endosomal recycling of the LDL receptor and transferrin receptor in hepatocytes

Khan, Taslima; Ginsburg, David; Emmer, Brian T.

doi:10.1016/j.jlr.2022.100248

Cited by 10 publications

(15 citation statements)

References 54 publications

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“…Module 255 also contains seven members of the exocyst complex, which is required for RAB10-mediated vesicle fusion with the plasma membrane 62 as well as three SNARE complex proteins known to be involved in exocytosis 62 . Altogether, this cluster implicates exocytosis in LDL-C uptake, in line with previous findings 23,63 .…”

Section: Resultssupporting

confidence: 91%

“…RAB10 is a multi-functional GTPase that has been implicated in a diverse array of vesicle-mediated processes including endocytosis and exocytosis 59,63 ; however, the co-essentiality data suggests stronger shared function with the exocyst complex than other vesicle-mediated processes, and we show that RAB10 pathway mutants show profoundly decreased LDLR membrane trafficking. The exocyst complex has been previously implicated in polarized transport of LDLR to basolateral membranes 66 , and mutations in exocyst genes impair LDLR uptake while increasing transferrin uptake 23 .…”

Section: Discussionmentioning

confidence: 60%

“…In our timecourse microscopy data, we are unable to detect substantial surface LDLR expression in RAB10-mutant cells at its earliest detectable timepoint, suggesting that impaired initial membrane trafficking indeed contributes to the phenotype. Recent work has also shown that RAB10-deficient cells show defective LDLR endosomal recycling as well 63 . Additionally, recent work has shown that RAB10 and exocyst knockout impairs LDL-C uptake in LDLR knockout cells 23,63 , and RAB10 has been implicated in lipophagy 97 , suggesting that this pathway's roles in lipid uptake and trafficking are multifaceted, going beyond LDLR membrane deposition.…”

Section: Discussionmentioning

confidence: 99%

“…Recent work has also shown that RAB10-deficient cells show defective LDLR endosomal recycling as well 63 . Additionally, recent work has shown that RAB10 and exocyst knockout impairs LDL-C uptake in LDLR knockout cells 23,63 , and RAB10 has been implicated in lipophagy 97 , suggesting that this pathway’s roles in lipid uptake and trafficking are multifaceted, going beyond LDLR membrane deposition. These additional roles of RAB10 may explain why the LDL-C exome burden within the enriched module clusters most strongly with RAB10 , RABIF , and its GEFs DENND4C and DENND4A and less so with exocyst genes.…”

Section: Discussionmentioning

confidence: 99%

See 3 more Smart Citations

Systematic elucidation of genetic mechanisms underlying cholesterol uptake

Hamilton

Fife

Akinci

et al. 2023

Preprint

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Genetic variation contributes greatly to LDL cholesterol (LDL-C) levels and coronary artery disease risk. By combined analysis of rare coding variants from the UK Biobank and genome-scale CRISPR-Cas9 knockout and activation screening, we have substantially improved the identification of genes whose disruption alters serum LDL-C levels. We identify 21 genes in which rare coding variants significantly alter LDL-C levels at least partially through altered LDL-C uptake. We use co-essentiality-based gene module analysis to show that dysfunction of the RAB10 vesicle transport pathway leads to hypercholesterolemia in humans and mice by impairing surface LDL receptor levels. Further, we demonstrate that loss of function ofOTX2leads to robust reduction in serum LDL-C levels in mice and humans by increasing cellular LDL-C uptake. Altogether, we present an integrated approach that improves our understanding of genetic regulators of LDL-C levels and provides a roadmap for further efforts to dissect complex human disease genetics.

show abstract

Section: Resultssupporting

confidence: 91%

Section: Discussionmentioning

confidence: 60%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Systematic elucidation of genetic mechanisms underlying cholesterol uptake

Hamilton

Fife

Akinci

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…Furthermore, they also found tens of genes that regulate total or cell surface level of LDLR by sorting LDLR-stained cells in a focused CRISPR screen ( Emmer et al, 2021 ). One of screening hit RAB10, a small GTPase, was later shown in a follow-up study to promote LDLR recycling from RAB11-positive endosomes to the plasma, thereby providing a mechanistic explanation on its role in LDL cholesterol uptake ( Khan et al, 2022 ). Interestingly, the function of RAB10 on LDL cholesterol regulation was further confirmed by another recent study in which several CRISPR screens were conducted with different focused libraries in human liver HepG2 cells to identify genes affecting LDL cholesterol uptake.…”

Section: Crispr Screening In Cardiovascular Researchmentioning

confidence: 99%

CRISPR screening in cardiovascular research

Shan

Teng

2023

Front. Cell Dev. Biol.

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The recent advent and widespread application of CRISPR-based genome editing tools have revolutionized biomedical research and beyond. Taking advantage of high perturbation efficiency and scalability, CRISPR screening has been regarded as one of the most powerful technologies in functional genomics which allows investigation of different genetic subjects at a large scale in parallel. Significant progress has been made using various CRISPR screening tools especially in cancer research, however, fewer attempts and less success are reported in other contexts. In this mini-review, we discuss how CRISPR screening has been implemented in studies on cardiovascular research and related metabolic disorders, highlight the scientific progress utilizing CRISPR screening, and further envision how to fully unleash the power of this technique to expedite scientific discoveries in these fields.

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Suspension culture promoted the expansion of NK‐92 cells ex vivo by enhancing the expression of IL‐2 receptor

Huang,

Zhang,

Zhao

et al. 2024

Biotechnology Journal

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Vigorous ex vivo expansion of NK‐92 cells is a pivotal step for clinical adoptive immunotherapy. Interleukin‐2 (IL‐2) is identified as a key cytokine for NK‐92 cells, and it can stimulate cell proliferation after binding to the IL‐2 receptor (IL‐2R). In this work, the differences in IL‐2 consumption and IL‐2R expression were investigated between the two culture modes. The results showed that suspension culture favored ex vivo expansion of NK‐92 cells compared with static culture. The specific consumption rate of IL‐2 in suspension culture was significantly higher than that in static culture. It was further found that the mRNA levels of the two IL‐2R subunits remained unchanged in suspension culture, but the proportion of NK‐92 cells expressing IL‐2Rβ was increased, and the fluorescence intensity of IL‐2Rβ was remarkably enhanced. Meanwhile, the proportion of cells expressing IL‐2R receptor complex also increased significantly. Correspondingly, the phosphorylation of STAT5, a pivotal protein in the downstream signaling pathway of IL‐2, was up‐regulated. Notably, the expression level and colocalization coefficient of related endosomes during IL‐2/IL‐2R complex endocytosis were markedly elevated, suggesting the enhancement of IL‐2 endocytosis. Taken together, these results implied that more IL‐2 was needed to support cell growth in suspension culture. Therefore, the culture process was optimized from the perspective of cytokine utilization to further improve the NK‐92 cell's expansion ability and function. This study provides valuable insight into the efficient ex vivo expansion of NK‐92 cells.

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The small GTPase RAB10 regulates endosomal recycling of the LDL receptor and transferrin receptor in hepatocytes

Cited by 10 publications

References 54 publications

Systematic elucidation of genetic mechanisms underlying cholesterol uptake

Systematic elucidation of genetic mechanisms underlying cholesterol uptake

CRISPR screening in cardiovascular research

Suspension culture promoted the expansion of NK‐92 cells ex vivo by enhancing the expression of IL‐2 receptor

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