GEF-H1 Mediated Control of NOD1 Dependent NF-κB Activation by Shigella Effectors

Fukazawa, Atsuko; Alonso, Carmen; Kurachi, Kiyotaka; Gupta, Sonal; Lesser, Cammie F.; McCormick, Beth A.; Reinecker, Hans Christian

doi:10.1371/journal.ppat.1000228

Cited by 101 publications

(109 citation statements)

References 57 publications

(68 reference statements)

Supporting

Mentioning

100

Contrasting

Order By: Relevance

“…The mechanisms by which these NLRs regulate DC function have not been determined. There is also precedent in other cell types for GEF-dependent NLR activation during bacterial cell invasion, although it is unknown whether this occurs via direct protein interaction (19). Therefore, it was possible that lack of DC migration in the NLRP10-deficient mice could result from positive regulation of DOCK8 by NLRP10; however, our subsequent studies in fact suggested that DOCK8 functions independent of NLRP10.…”

Section: Resultsmentioning

confidence: 89%

Coincidental loss of DOCK8 function in NLRP10-deficient and C3H/HeJ mice results in defective dendritic cell migration

Krishnaswamy¹,

Singh²,

Gowthaman³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Dendritic cells (DCs) are the primary leukocytes responsible for priming T cells. To find and activate naïve T cells, DCs must migrate to lymph nodes, yet the cellular programs responsible for this key step remain unclear. DC migration to lymph nodes and the subsequent T-cell response are disrupted in a mouse we recently described lacking the NOD-like receptor NLRP10 (NLR family, pyrin domain containing 10); however, the mechanism by which this pattern recognition receptor governs DC migration remained unknown. Using a proteomic approach, we discovered that DCs from Nlrp10 knockout mice lack the guanine nucleotide exchange factor DOCK8 (dedicator of cytokinesis 8), which regulates cytoskeleton dynamics in multiple leukocyte populations; in humans, loss-of-function mutations in Dock8 result in severe immunodeficiency. Surprisingly, Nlrp10 knockout mice crossed to other backgrounds had normal DOCK8 expression. This suggested that the original Nlrp10 knockout strain harbored an unexpected mutation in Dock8, which was confirmed using whole-exome sequencing. Consistent with our original report, NLRP3 inflammasome activation remained unaltered in NLRP10-deficient DCs even after restoring DOCK8 function; however, these DCs recovered the ability to migrate. Isolated loss of DOCK8 via targeted deletion confirmed its absolute requirement for DC migration. Because mutations in Dock genes have been discovered in other mouse lines, we analyzed the diversity of Dock8 across different murine strains and found that C3H/HeJ mice also harbor a Dock8 mutation that partially impairs DC migration. We conclude that DOCK8 is an important regulator of DC migration during an immune response and is prone to mutations that disrupt its crucial function.D endritic cells (DCs) are crucial for the initiation of an adaptive immune response. Upon acquiring antigens in the periphery, DCs undergo a maturation process that includes antigen processing, cytokine production, and up-regulation of costimulatory molecules. A mature DC must then migrate from peripheral tissues to draining lymph nodes (LNs) to fulfill its role as an antigen-presenting cell that primes naïve T cells (1). Although the signals that induce this maturation process are now well-established (1), relatively little is understood about DC migration aside from the primary chemotactic cue provided by CCR7 that guides DCs to the LN (2, 3).We recently described a genetically modified NLRP10 (NLR family, pyrin domain containing 10) knockout strain in which this migration step was disrupted while leaving the remainder of the DC maturation program, including CCR7 expression, intact (4).NLRP10 is the only NOD-like receptor (NLR) without a leucine-rich repeat domain, the putative pathogen-associated molecular pattern (PAMP)-binding domain. It has been proposed to both positively and negatively regulate other NLRs, such as NOD1 and NLRP3, respectively (5, 6). Although we found that NLRP3 inflammasome activation was unaltered in the absence of NLRP10, we discovered that Nlrp10 −/− mice could ...

show abstract

Section: Resultsmentioning

confidence: 89%

Coincidental loss of DOCK8 function in NLRP10-deficient and C3H/HeJ mice results in defective dendritic cell migration

Krishnaswamy¹,

Singh²,

Gowthaman³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…GEF-H1 is also activated by various pathogens, junction dissociation, and tissue disruption (28,30,40,41). Moreover, ZONAB is stimulated by reduced expression of ZO-1, a cellular inhibitor of the transcriptional and posttranscriptional function of ZONAB, linking it to the integrity of tight junctions (10).…”

Section: Discussionmentioning

confidence: 99%

Stress- and Rho-activated ZO-1–associated nucleic acid binding protein binding to p21 mRNA mediates stabilization, translation, and cell survival

Nie

Balda

Matter

2012

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

A central component of the cellular stress response is p21 WAF1/CIP1 , which regulates cell proliferation, survival, and differentiation. Inflammation and cell stress often up-regulate p21 posttranscriptionally by regulatory mechanisms that are poorly understood. ZO-1-associated nucleic acid binding protein (ZONAB)/DbpA is a Y-box transcription factor that is regulated by components of intercellular junctions that are affected by cytokines and tissue damage. We therefore asked whether ZONAB activation is part of the cellular stress response. Here, we demonstrate that ZONAB promotes cell survival in response to proinflammatory, hyperosmotic, and cytotoxic stress and that stress-induced ZONAB activation involves the Rho regulator GEF-H1. Unexpectedly, stress-induced ZONAB activation does not stimulate ZONAB's activity as a transcription factor but leads to the posttranscriptional up-regulation of p21 protein and mRNA. Up-regulation is mediated by ZONAB binding to specific sites in the 3′-untranslated region of the p21 mRNA, resulting in mRNA stabilization and enhanced translation. Binding of ZONAB to mRNA is activated by GEF-H1 via Rho stimulation and also mediates Ras-induced p21 expression. We thus identify a unique type of stress and Rho signaling activated pathway that drives mRNA stabilization and translation and links the cellular stress response to p21 expression and cell survival.epithelia | RhoGTPases | tight junction | necrosis | apoptosis C ells developed regulatory pathways that are activated in response to proinflammatory challenges, adverse extracellular conditions, and cytotoxic stress to ensure cell survival and tissue integrity. These pathways regulate expression of genes encoding factors required to cope with stress conditions and involve transcription factors that stimulate the synthesis of mRNAs encoding proteins required for specific responses. However, expression of many crucial stress-induced genes is regulated posttranscriptionally by mechanisms that are not well understood.A central regulator of cell proliferation and survival is p21 WAF1/CIP1

show abstract

“…Alternatively, the lack of amplified IL-8 production or MAPK activation following NOD1 and/or RICK over-expression may suggest the involvement of additional signaling molecules, which are required for initial host responses to H. pylori. Indeed, Fukazawa et al (70), recently found that the guanine nucleotide exchange factor was critical for the NOD1-dependent signaling responses to S. flexneri. It may be that molecules such as guanine nucleotide exchange factor are also required for the initiation of NOD1-mediated proinflammatory signal cascades during H. pylori infection.…”

Section: Discussionmentioning

confidence: 99%

Helicobacter pyloriInduces MAPK Phosphorylation and AP-1 Activation via a NOD1-Dependent Mechanism

Allison

Kufer

Kremmer

et al. 2009

The Journal of Immunology

157

161

View full text Add to dashboard Cite

show abstract

GEF-H1 Mediated Control of NOD1 Dependent NF-κB Activation by Shigella Effectors

Cited by 101 publications

References 57 publications

Coincidental loss of DOCK8 function in NLRP10-deficient and C3H/HeJ mice results in defective dendritic cell migration

Coincidental loss of DOCK8 function in NLRP10-deficient and C3H/HeJ mice results in defective dendritic cell migration

Stress- and Rho-activated ZO-1–associated nucleic acid binding protein binding to p21 mRNA mediates stabilization, translation, and cell survival

Helicobacter pyloriInduces MAPK Phosphorylation and AP-1 Activation via a NOD1-Dependent Mechanism

Contact Info

Product

Resources

About