Coordination between Rac1 and Rab Proteins: Functional Implications in Health and Disease

Margiotta, Azzurra; Bucci, Cecilia

doi:10.3390/cells8050396

Cited by 28 publications

(25 citation statements)

References 137 publications

(228 reference statements)

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“…An alternative possibility is that EIPA inhibits VSVΔG-BHLD entry due to its previously described pleiotropic effect manifested as gross reorganization of the endosomal network and changes in Na + and H + gradients in the cell (71, 72). Similarly, inhibition of Rac1 by NSC23766 could have a pleotropic effect because Rac1, in addition to its roles in regulating the actin cytoskeleton, is also involved in several other cellular processes (73).…”

Section: Discussionmentioning

confidence: 99%

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Contributions of the four essential entry glycoproteins to HSV-1 tropism and the selection of entry routes

Hilterbrand

Daly

Heldwein

2020

Preprint

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15Herpes Simplex viruses (HSV-1 and HSV-2) encode up to 15 glycosylated and unglycosylated 16 envelope proteins. Four of these, gB, gH, gL, and gD, are essential for entry and mediate cell-cell 17 fusion when co-expressed in uninfected, receptor-bearing cells. However, their contributions to 18 HSV-1 tropism and the selection of entry routes are unclear. To begin addressing this, we 19 previously pseudotyped VSV lacking its native glycoprotein, G, with HSV-1 glycoproteins gB, 20 gH, gL, and gD. This novel VSVDG-BHLD pseudotype recapitulated several aspects of HSV-1 21 entry: it could enter murine C10 cells, required gB, gH, gL, gD, and a cellular receptor for entry, 22 AUTHOR SUMMARY 37Different viruses enter cells by diverse routes, but how that choice is made is not always clear. 38Understanding the mechanisms behind these choices is vital for finding strategies to prevent viral 39 infections. In enveloped viruses, viral proteins embedded in the envelope accomplish this task. 40While most enveloped viruses encode one or two envelope proteins, Herpes Simplex viruses 41 (HSV) encode up to 15. Four of these are deemed essential for entry (gB, gH, gL, and gD) 42 whereas the rest have been termed non-essential. While these four proteins are essential, their 43 contributions to HSV-1 cellular tropism and entry pathways have not been fully elucidated. Here, 44we generated virions that have only the four essential HSV-1 glycoproteins on their surface. We 45show that the VSVDG-BHLD pseudotype has a narrower tropism than HSV-1 and uses different 46 entry pathways. Thus, the four essential HSV-1 entry glycoproteins alone do not define HSV-1 47 55All viruses must enter cells to initiate infection, and different viruses accomplish this task by 56 different mechanisms: some penetrate cells at the plasma membrane while others hijack host 57 endocytic pathways. Enveloped viruses -those in which the nucleocapsid is surrounded by a 58 cell-derived lipid bilayer -penetrate the cells by merging their lipid envelopes with a cellular 59 membrane, either the plasma membrane or the membrane of an endocytic vesicle following 60 endocytosis ( Fig 1) [reviewed in (1, 2)]. Viruses typically have preferred entry routes, the choice 61 of which is not always clear, and some enter different target cells by different routes. 62Understanding what routes viruses use to enter cells and how they select them may help inform 63 strategies to prevent viral infections. 64Herpes Simplex viruses (HSV-1 and HSV-2) are enveloped alphaherpesviruses that infect 65 much of the world's population for life, causing a panoply of diseases ranging from painful to 66 life-threatening (3, 4). An enduring mystery of HSV entry is how and why the virus enters 67 different cells by different routes: direct fusion with the plasma membrane [e.g., neurons, Vero 68 cells, Hep2 cells, reviewed in (5)] or by endocytosis and subsequent fusion with the endosomal 69 membrane [e.g., keratinocytes, corneal epithelial cells (6, 7)]. 70HSV-1 encodes 15 viral envelope proteins, ...

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Section: Discussionmentioning

confidence: 99%

“…EIPA treatment can lead to a gross reorganization of the endosomal network and changes in Na + and H + gradients in the cell (94, 95). Similarly, Rac1, the target of NSC23766, is involved in several cellular processes in addition to regulating the actin cytoskeleton (96).…”

Section: Discussionmentioning

confidence: 99%

Contributions of the four essential entry glycoproteins to HSV-1 tropism and the selection of entry routes

Hilterbrand

Daly

Heldwein

2020

Preprint

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“…The expression pro les of ARLs are rstly explored using TCGA, GTEx and Oncomine databases, which demonstrate that ARLs are commonly dysregulated in GC. Accumulating evidences suggest that the cross-talk and collaboration between small GTPase proteins are causatively involved in several cellular processes and diseases (24)(25)(26)(27). In this study, co-expression and correlation analyses demonstrate that the expression levels of ARLs in GC show high correlations.…”

Section: Discussionmentioning

confidence: 99%

ARL4C is A Key Driver of Gastric Cancer: An Integrative Analysis of ARL Family Members

Xie¹,

Bai²,

Lu³

et al. 2020

Preprint

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Background: As small GTP-binding proteins, ARL family members (ARLs) have been proved to regulate the malignant phenotypes of several cancers. However, the exact role of ARLs in gastric cancer (GC) remains elusive.Methods: The expression status, interactive relations, potential pathways and genetic variations of ARLs are analyzed by bioinformatics tools. Machine learning models and enrichment analysis are performed by R platform. The biological functions of ARL4C are demonstrated by in vitro and in vivo experiments. The nomogram is further constructed to validate the prognostic value of ARL4C for GC patients.Results: ARLs are significantly dysregulated in GC and involved in various cancer-related pathways. Subsequently, machine learning models identify ARL4C as one of the two most significant diagnostic and prognostic indicators among ARLs for GC. Furthermore, ARL4C silencing remarkably reverses the epithelial-mesenchymal transition (EMT) and inhibits the growth and metastasis of GC cells both in vitro and in vivo. Moreover, enrichment analysis indicates that TGF-β1 is highly correlated with ARL4C, while ARL4C-related genes are significantly enriched in the TGF-β1 signaling. Correspondingly, we demonstrate that TGF-β1 treatment dramatically increases ARL4C expression, and ARL4C knockdown reverses TGF-β1-induced EMT possibly by inhibiting the expression of Smads, downstream factors of TGF-β1. Meanwhile, the coexpression of ARL4C and TGF-β1 worsens the prognosis of GC patients both in Kaplan-Meier analysis and nomogram model.Conclusion: Our work is of significance for comprehensively understanding the crucial role of ARLs in the carcinogenesis of GC and the specific mechanisms underlying the GC-promoting effects of TGF-β1. More importantly, we uncover the great promise of ARL4C-targeted therapy in improving the efficacy of TGF-β1 inhibitors for GC patients.

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“…Therefore, an attractive mechanism for the timely remodeling of local actin cytoskeletal networks in concert with dynamic changes of membranes may be efficient coordination of Rho and Rab GTPases. Indeed, evidence is emerging that reveals an interplay between Rab and Rho GTPases [8,9].…”

Section: Introductionmentioning

confidence: 99%

Kalirin Interacts with TRAPP and Regulates Rab11 and Endosomal Recycling

Wang

Weng

et al. 2020

Cells

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Coordinated actions of Rab and Rho are necessary for numerous essential cellular processes ranging from vesicle budding to whole cell movement. How Rab and Rho are choreographed is poorly understood. Here, we report a protein complex comprised of kalirin, a Rho guanine nucleotide exchange factor (GEF) activating Rac1, and RabGEF transport protein particle (TRAPP). Kalirin was identified in a mass spectrometry analysis of proteins precipitated by trappc4 and detected on membranous organelles containing trappc4. Acute knockdown of kalirin did not affect trappc4, but significantly reduced overall and membrane-bound levels of trappc9, which specifies TRAPP toward activating Rab11. Trappc9 deficiency led to elevated expression of kalirin in neurons. Co-localization of kalirin and Rab11 occurred at a low frequency in NRK cells under steady state and was enhanced upon expressing an inactive Rab11 mutant to prohibit the dissociation of Rab11 from the kalirin-TRAPP complex. The small RNA-mediated depletion of kalirin diminished activities in cellular membranes for activating Rab11 and resulted in a shift in size of Rab11 positive structures from small to larger ones and tubulation of recycling endosomes. Our study suggests that kalirin and TRAPP form a dual GEF complex to choreograph actions of Rab11 and Rac1 at recycling endosomes.

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Coordination between Rac1 and Rab Proteins: Functional Implications in Health and Disease

Cited by 28 publications

References 137 publications

Contributions of the four essential entry glycoproteins to HSV-1 tropism and the selection of entry routes

Contributions of the four essential entry glycoproteins to HSV-1 tropism and the selection of entry routes

ARL4C is A Key Driver of Gastric Cancer: An Integrative Analysis of ARL Family Members

Kalirin Interacts with TRAPP and Regulates Rab11 and Endosomal Recycling

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