<scp>TLR</scp> sorting by <scp>R</scp>ab11 endosomes maintains intestinal epithelial‐microbial homeostasis

Yu, Shiyan; Nie, Yulun; Knowles, Byron C.; Sakamori, Ryotaro; Stypulkowski, Ewa; Patel, Chirag; Das, Soumyashree; Douard, Véronique; Ferraris, Ronaldo P.; Bonder, Edward M.; Goldenring, James R.; Ip, Y. Tony; Gao, Nan

doi:10.15252/embj.201487888

Cited by 56 publications

(82 citation statements)

References 58 publications

(84 reference statements)

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“…In particular, Rab11 has been proposed to regulate ligand-initiated signaling through the control of receptor recycling (34), the activation of distant regulatory pathways via the secretion of exosomes (44) and the control of inflammatory responses through the regulation of endosomal receptor trafficking and sorting (45). Our data support the view that Rab11 is important for the correct function of immune cells and, in particular, suggest that Rab11 regulates neutrophil exocytosis and ROS production, two essential neutrophil innate immune responses.…”

Section: Discussionmentioning

confidence: 99%

Munc13-4 Is a Rab11-binding Protein That Regulates Rab11-positive Vesicle Trafficking and Docking at the Plasma Membrane

Johnson¹,

He²,

Ramadass³

et al. 2016

Journal of Biological Chemistry

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The small GTPase Rab11 and its effectors control trafficking of recycling endosomes, receptor replenishment and the up-regulation of adhesion and adaptor molecules at the plasma membrane. Despite recent advances in the understanding of Rab11-regulated mechanisms, the final steps mediating docking and fusion of Rab11-positive vesicles at the plasma membrane are not fully understood. Munc13-4 is a docking factor proposed to regulate fusion through interactions with SNAREs. In hematopoietic cells, including neutrophils, Munc13-4 regulates exocytosis in a Rab27a-dependent manner, but its possible regulation of other GTPases has not been explored in detail. Here, we show that Munc13-4 binds to Rab11 and regulates the trafficking of Rab11-containing vesicles. Using a novel Time-resolved Fluorescence Resonance Energy Transfer (TR-FRET) assay, we demonstrate that Munc13-4 binds to Rab11a but not to dominant negative Rab11a. Immunoprecipitation analysis confirmed the specificity of the interaction between Munc13-4 and Rab11, and super-resolution microscopy studies support the interaction of endogenous Munc13-4 with Rab11 at the single molecule level in neutrophils. Vesicular dynamic analysis shows the common spatio-temporal distribution of Munc13-4 and Rab11, while expression of a calcium binding-deficient mutant of Munc13-4 significantly affected Rab11 trafficking. Munc13-4-deficient neutrophils showed normal endocytosis, but the trafficking, upregulation, and retention of Rab11-positive vesicles at the plasma membrane was significantly impaired. This correlated with deficient NADPH oxidase activation at the plasma membrane in response to Rab11 interference. Our data demonstrate that Munc13-4 is a Rab11-binding partner that regulates the final steps of Rab11-positive vesicle docking at the plasma membrane.Rab GTPases are membrane organizers that regulate the specificity of subcellular compartments and trafficking of these compartments through interactions with specific effectors (1). In particular, Rab11, a ubiquitously expressed GTPase, has been implicated in the regulation of several intracellular mechanisms including recycling endosome trafficking, transport of cargo from the sorting endosomes and the trans-Golgi network to the endosomal recycling compartment and regulation of trafficking during cytokinesis (2). In addition, the Rab11 family of GTPases, comprised by Rab11a, Rab11b and Rab11c/Rab25, are known to regulate several cellular functions including exocytosis (3), phagocytosis (4), and cell-cell communication (5). Rab11 functions are regulated by a broad range of molecular interactors and effectors (2), and proteomic analyses have identified a large array of structurally diverse molecules that interact with Rab11. The most studied family of Rab11 effectors, FIPs (Rab11 family-interacting proteins), 4 comprises five members. Rip11, FIP2, and RCP are characterized by the presence of a conserved Rab11-binding domain at their C terminus and a C2 domain at their N terminus, and FIP3 and FIP4 are characterized by t...

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Section: Discussionmentioning

confidence: 99%

Munc13-4 Is a Rab11-binding Protein That Regulates Rab11-positive Vesicle Trafficking and Docking at the Plasma Membrane

Johnson¹,

He²,

Ramadass³

et al. 2016

Journal of Biological Chemistry

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“…Two loxP sites were then introduced sequentially at 242 bp downstream of the second exon and 210 bp downstream of the fourth exon of Rab11a, respectively (35). The sequence-verified targeting vector was linearized with ClaI digestion and electroporated into R1 embryonic stem cells.…”

Section: Derivation Of the Mouse Rab11amentioning

confidence: 99%

Global Ablation of the Mouse Rab11a Gene Impairs Early Embryogenesis and Matrix Metalloproteinase Secretion

Yehia

Wang

et al. 2014

Journal of Biological Chemistry

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Background:The physiological role of Rab11a in mouse embryogenesis has not been fully studied. Results: Using a Rab11a null mouse allele, the transport of multiple membrane-associated and soluble cargos was analyzed in mouse blastocysts and MEFs. Conclusion: Rab11a ablation impairs mouse blastocyst development and the secretion of soluble matrix metalloproteinases. Significance: In vivo functions of Rab11a in mouse fetal development and soluble MMP secretion were uncovered.

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“…In this study, we report that Rab11a regulates apical intestinal enterocyte polarity. Utilizing mice with a Rab11a-knockout specific to intestinal epithelial cells (Rab11a Rab11a expression specifically in intestinal epithelial cells (Yu et al, 2014a). Previous work published by our laboratory has demonstrated that MYO5B-coupled Rab11a-dependent trafficking is required for proper apical trafficking and brush border maintenance in enterocytes (Knowles et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Rab11a regulates Syntaxin 3 localization and microvillus assembly in enterocytes

Knowles

Weis

et al. 2015

Journal of Cell Science

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Rab11a is a key component of the apical recycling endosome that aids in the trafficking of proteins to the luminal surface in polarized epithelial cells. Utilizing conditional Rab11a-knockout specific to intestinal epithelial cells, and human colonic epithelial CaCo2-BBE cells with stable Rab11a knockdown, we examined the molecular and pathological impact of Rab11a deficiency on the establishment of apical cell polarity and microvillus morphogenesis. We demonstrate that loss of Rab11a induced alterations in enterocyte polarity, shortened microvillar length and affected the formation of microvilli along the lateral membranes. Rab11a deficiency in enterocytes altered the apical localization of syntaxin 3. These data affirm the role of Rab11a in apical membrane trafficking and the maintenance of apical microvilli in enterocytes.

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TLR sorting by Rab11 endosomes maintains intestinal epithelial‐microbial homeostasis

Cited by 56 publications

References 58 publications

Munc13-4 Is a Rab11-binding Protein That Regulates Rab11-positive Vesicle Trafficking and Docking at the Plasma Membrane

Munc13-4 Is a Rab11-binding Protein That Regulates Rab11-positive Vesicle Trafficking and Docking at the Plasma Membrane

Global Ablation of the Mouse Rab11a Gene Impairs Early Embryogenesis and Matrix Metalloproteinase Secretion

Rab11a regulates Syntaxin 3 localization and microvillus assembly in enterocytes

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