Selectivity of Guanine Nucleotide Exchange Factor-mediated Cdc42 activation in primary human endothelial cells

Nr, Reinhard; Sv, der Niet; Chertkova, Anna O.; Postma, Marten; Hordijk, Peter L.; Tw, Gadella; Goedhart, Joachim

doi:10.1101/541219

Cited by 3 publications

(3 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Alternatively, ARHGEF26-mediated invasion may involve other small GTPases. For instance, ARHGEF26 does show a weak capacity to stimulate nucleotide exchange of CDC42 and RAC1 in vitro (45,46). Alternatively, ARHGEF26 could activate other CDC42related small-GTPases, such as RHOJ, which have recently been shown to affect invasion (19,47).…”

Section: Rhog Knockdown Does Not Phenocopy Arhgef26 Knockdownmentioning

confidence: 99%

“…However, many PH domains either completely lack canonical phosphoinositide binding or have phosphoinositide binding that is physiologically irrelevant (50,54). Therefore, PHdependence alone is insufficient to implicate SopB-generated phosphoinositides as this could suggest either that ARHGEF26 binds phosphoinositides in order to function, or simply, that this mutation disrupts the catalytic domain as has been shown for other RHO GEFs (46).…”

mentioning

confidence: 99%

See 1 more Smart Citation

ARHGEF26 enhancesSalmonellainvasion and inflammation in cells and mice

Bourgeois

Wang

Alvarez

et al. 2020

Preprint

View full text Add to dashboard Cite

Salmonella hijack host machinery in order to invade cells and establish infection. While considerable work has described the role of host proteins in invasion, much less is known regarding how natural variation in these invasion-associated host proteins affects Salmonella pathogenesis. Here we leveraged a candidate cellular GWAS screen to identify natural genetic variation in the ARHGEF26 (Rho Guanine Nucleotide Exchange Factor 26) gene that renders lymphoblastoid cells susceptible to Salmonella Typhi and Typhimurium invasion. Experimental follow-up redefined ARHGEF26’s role in Salmonella epithelial cell invasion, identified serovar specific interactions, implicated ARHGEF26 in SopE-mediated invasion, and revealed that the ARHGEF26-associated proteins DLG1 and SCRIB facilitate S. Typhi uptake. Importantly, we show that ARHGEF26 plays a critical role in S. Typhimurium pathogenesis by contributing to bacterial burden in the enteric fever murine model, as well as inflammation in the gastroenteritis infection model. The impact of ARHGEF26 on inflammation was also seen in cells, as knockdown reduced IL-8 production in HeLa cells. Together, these data reveal pleiotropic roles for ARHGEF26 function during infection and highlight that many of the interactions that occur during infection that are thought to be well understood likely have underappreciated complexity.Author SummaryDuring infection, Salmonella manipulates host cells into engulfing the bacteria and establishing an intracellular niche. While many studies have identified genes involved in different stages of this Salmonella invasion process, few studies have examined how differences between human hosts contribute to infection susceptibility. Here we leveraged a candidate genetic screen to identify natural genetic variation in the human ARHGEF26 gene that correlates with Salmonella invasion. Springboarding from this result, we experimentally tested and revised existing models of ARHGEF26’s role in Salmonella invasion, discovered an additional new role for ARHGEF26 during Salmonella disease, and confirmed our findings in mouse models. Building on how ARHGEF26 functions in other contexts, we implicated two ARHGEF26-interacting host proteins as contributors to Salmonella pathobiology. Collectively, these results identify a potential source of inter-person diversity in susceptibility to Salmonella disease, expand our molecular understanding of Salmonella infection to include a multifaceted role for ARHGEF26, and identify several important future directions that will be important to understand how Salmonella recruit and manipulate ARHGEF26 as well as how ARHGEF26 is able to drive Salmonella-beneficial processes.

show abstract

Section: Rhog Knockdown Does Not Phenocopy Arhgef26 Knockdownmentioning

confidence: 99%

mentioning

confidence: 99%

ARHGEF26 enhancesSalmonellainvasion and inflammation in cells and mice

Bourgeois

Wang

Alvarez

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…shown to be one of the RhoGEFs that activate Rac and Cdc42, while a later study reported that PLEKHG1 is one of the RhoGEFs that activate Cdc42 (20,21). However, the details of the regulation of PLEKHG1 within cells, including the involvement of SFKs, are not known.…”

Section: Introductionmentioning

confidence: 99%

The Rho guanine nucleotide exchange factor PLEKHG1 is activated by interaction with and phosphorylation by Src family kinase member FYN

Nakano

Nishikawa

Kobayashi

et al. 2022

Journal of Biological Chemistry

View full text Add to dashboard Cite

This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

show abstract

Spatiotemporal Control of Intracellular Membrane Trafficking by Rho GTPases

Noll

Haußer

2019

Cells

View full text Add to dashboard Cite

As membrane-associated master regulators of cytoskeletal remodeling, Rho GTPases coordinate a wide range of biological processes such as cell adhesion, motility, and polarity. In the last years, Rho GTPases have also been recognized to control intracellular membrane sorting and trafficking steps directly; however, how Rho GTPase signaling is regulated at endomembranes is still poorly understood. In this review, we will specifically address the local Rho GTPase pools coordinating intracellular membrane trafficking with a focus on the endo-and exocytic pathways. We will further highlight the spatiotemporal molecular regulation of Rho signaling at endomembrane sites through Rho regulatory proteins, the GEFs and GAPs. Finally, we will discuss the contribution of dysregulated Rho signaling emanating from endomembranes to the development and progression of cancer.an inactive GDP-bound and an active GTP-bound state. Rho GDP/GTP cycling is tightly regulated by guanine nucleotide exchange factors (GEFs) that promote the formation of the active GTP-bound form through exchanging GDP for GTP. On the contrary, GTPase-activating proteins (GAPs) catalyze the intrinsic GTPase activity and promote the formation of inactive GDP-bound Rho. This inactive state can be subsequently recognized by guanine nucleotide dissociation inhibitors (GDIs), which sequester Rho GTPases in the cytosol [5,6] (Figure 1). Whereas classical Rho GTPases are regulated by GDP/GTP cycling, atypical Rho GTPases are regulated by other mechanisms that occur in particular at the transcriptional and post-translational level [7]. In the case of atypical Rho GTPases, GTP is usually constitutively bound, either because these Rho GTPases possess high intrinsic nucleotide exchange activity or have substitutions in their GTPase domain that prevent GTP hydrolysis.

show abstract

Selectivity of Guanine Nucleotide Exchange Factor-mediated Cdc42 activation in primary human endothelial cells

Cited by 3 publications

References 39 publications

ARHGEF26 enhancesSalmonellainvasion and inflammation in cells and mice

ARHGEF26 enhancesSalmonellainvasion and inflammation in cells and mice

The Rho guanine nucleotide exchange factor PLEKHG1 is activated by interaction with and phosphorylation by Src family kinase member FYN

Spatiotemporal Control of Intracellular Membrane Trafficking by Rho GTPases

Contact Info

Product

Resources

About