The Rab11a GTPase Controls Toll-like Receptor 4-Induced Activation of Interferon Regulatory Factor-3 on Phagosomes

Husebye, Harald; Aune, Marie; Stenvik, Jørgen; Samstad, Eivind; Skjeldal, Frode Miltzow; Halaas, Øyvind; Nilsen, Nadra J.; Stenmark, Harald; Latz, Eicke; Lien, Egil; Mollnes, Tom Eirik; Bakke, Oddmund; Espevik, Terje

doi:10.1016/j.immuni.2010.09.010

Cited by 178 publications

(228 citation statements)

References 36 publications

Supporting

Mentioning

210

Contrasting

Order By: Relevance

“…Further specificity may be achieved through autonomous control by phagosomes in contributing pMHCII for presentation, meaning that antigens are preferentially presented by MHCII when originating from antigen-carrying particles that also stimulate DC-activating receptors from within that same compartment (Blander and Medzhitov 2006;Hoffmann et al 2012). This idea is supported by the observations that TLR2 (Underhill et al 1999) and TLR4 (Husebye et al 2010;Mantegazza et al 2012) can be recruited to and signal from phagosomes. TLR delivery to phagosomes requires the clathrin adaptor AP-3, and local signaling facilitates pMHCII recruitment from phagosomes for presentation at the plasma membrane (Mantegazza et al 2012).…”

Section: Autonomous Phagosomesmentioning

confidence: 75%

MHC Class II Antigen Presentation by Dendritic Cells Regulated through Endosomal Sorting

Broeke

Wubbolts

Stoorvogel

2013

Cold Spring Harbor Perspectives in Biology

134

View full text Add to dashboard Cite

For the initiation of adaptive immune responses, dendritic cells present antigenic peptides in association with major histocompatibility complex class II (MHCII) to naïve CD4 þ T lymphocytes. In this review, we discuss how antigen presentation is regulated through intracellular processing and trafficking of MHCII. Newly synthesized MHCII is chaperoned by the invariant chain to endosomes, where peptides from endocytosed pathogens can bind. In nonactivated dendritic cells, peptide-loaded MHCII is ubiquitinated and consequently sorted by the ESCRT machinery to intraluminal vesicles of multivesicular bodies, ultimately leading to lysosomal degradation. Ubiquitination of newly synthesized MHCII is blocked when dendritic cells are activated, now allowing its transfer to the cell surface. This mode of regulation for MHCII is a prime example of how molecular processing and sorting at multivesicular bodies can determine the expression of signaling receptors at the plasma membrane.

show abstract

Section: Autonomous Phagosomesmentioning

confidence: 75%

MHC Class II Antigen Presentation by Dendritic Cells Regulated through Endosomal Sorting

Broeke

Wubbolts

Stoorvogel

2013

Cold Spring Harbor Perspectives in Biology

134

View full text Add to dashboard Cite

show abstract

“…Discussion TLR4 endocytosis and trafficking to the endosomal compartment is important for the regulation of TRIF-mediated signaling induced by LPS (8,33). This process is tightly regulated by dynamins, clathrin, and associated Rab proteins (9,34). Kagan and coworkers reported that, upon LPS stimulation, TLR4 is recruited to the endosome from the plasma membrane where it interacts with TRAM and TRIF adaptor molecules, leading to activation of the IRF3 pathway (8).…”

Section: Cd14-independent Endocytosis Of Tlr4 In Macrophages Renderedmentioning

confidence: 99%

CD14 dependence of TLR4 endocytosis and TRIF signaling displays ligand specificity and is dissociable in endotoxin tolerance

Rajesh

Perkins

Ireland

et al. 2015

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

119

104

View full text Add to dashboard Cite

Dimerization of Toll-like receptor 4 (TLR4)/myeloid differentiation factor 2 (MD2) heterodimers is critical for both MyD88-and TIRdomain-containing adapter-inducing IFN-β (TRIF)-mediated signaling pathways. Recently, Zanoni et al. [(2011) Cell 147(4):868-880] reported that cluster of differentiation 14 (CD14) is required for LPS-/Escherichia coli-induced TLR4 internalization into endosomes and activation of TRIF-mediated signaling in macrophages. We confirmed their findings with LPS but report here that CD14 is not required for receptor endocytosis and downstream signaling mediated by TLR4/MD2 agonistic antibody (UT12) and synthetic small-molecule TLR4 ligands (1Z105) in murine macrophages. CD14 deficiency completely ablated the LPS-induced TBK1/IRF3 signaling axis that mediates production of IFN-β in murine macrophages without affecting MyD88-mediated signaling, including NF-κB, MAPK activation, and TNF-α and IL-6 production. However, neither the MyD88-nor TRIF-signaling pathways and their associated cytokine profiles were altered in the absence of CD14 in UT12-or 1Z105-treated murine macrophages. Eritoran (E5564), a lipid A antagonist that binds the MD2 "pocket," completely blocked LPS-and 1Z105-driven, but not UT12-induced, TLR4 dimerization and endocytosis. Furthermore, TLR4 endocytosis is induced in macrophages tolerized by exposure to either LPS or UT12 and is independent of CD14. These data indicate that TLR4 receptor endocytosis and the TRIF-signaling pathway are dissociable and that TLR4 internalization in macrophages can be induced by UT12, 1Z105, and during endotoxin tolerance in the absence of CD14. T oll-like receptor 4 (TLR4) signaling plays a crucial role in host defense against Gram-negative bacteria by recognizing the outer membrane component, lipopolysaccharide (LPS) (1-3). TLR4 signaling is initiated by transfer of an LPS monomer from LPS binding protein (LBP) to cluster of differentiation 14 (CD14) (GPI-linked or soluble). In turn, CD14 transfers monomeric LPS to myeloid differentiation factor 2 (MD-2), a protein that associates noncovalently with TLR4 (4). Appropriate ligand binding to MD2 results in dimerization of two TLR4/MD2 complexes (4). TLR4 is unique in that it is the only TLR that activates both myeloid differentiation primary response 88 (MyD88) and TIR-domain-containing adapter-inducing IFN-β (TRIF)-dependent signaling pathways (5, 6). MyD88-mediated, TLR4 signaling occurs mainly at plasma membranes and involves IL-1R-associated kinases phosphorylation, association of TNF-receptor-associated factor 6, and downstream signaling that results in NF-κB activation and induction of proinflammatory mediators such as TNF-α and IL-6 (7). In contrast, TRIF-mediated signaling in response to LPS occurs at the endosomal membrane after internalization of the TLR4 that, in turn, activates IFN regulatory factor 3 (IRF3), resulting in production of IFN-β, IP-10, and other IRF-3-dependent genes, as well as delayed NF-κB activation (8). Recent studies have shown that the endocytosis of TLR4 is tight...

show abstract

“…4A, highlighted by white arrow). In the absence of Btk however, CRT becomes sequestered in distinct cellular compartments proximal to the nucleus similar to the endocytic recycling compartment (ERC) (28). These results indicate that Btk regulates the relocalization of CRT within the cell following TLR7 stimulation and that the ablation of Btk results in the dysregulation of CRT trafficking in response to extracellular stimuli.…”

Section: Btk Interacts With and Directly Phosphorylates Crt Followingmentioning

confidence: 90%

Bruton's Tyrosine Kinase Is Required for Apoptotic Cell Uptake via Regulating the Phosphorylation and Localization of Calreticulin

Byrne

Gabhann

Stacey

et al. 2013

The Journal of Immunology

View full text Add to dashboard Cite

In addition to regulating B cell development and activation, Bruton’s tyrosine kinase (Btk) functions downstream of multiple TLRs, including TLR7, to regulate innate immune responses in myeloid cells. Although critical for defense against RNA viruses such as influenza and Sendai virus, recognition of self-RNA by TLR7 also has been shown to be an important contributor to the pathophysiology of systemic lupus erythematosus. To date, the role of Btk in regulating TLR7-mediated responses is poorly understood. In the current study, we have demonstrated a hitherto undiscovered role for Btk in apoptotic cell uptake, identifying the molecular chaperone calreticulin (CRT) as a novel substrate for Btk in regulating this response. CRT together with the transmembrane receptor CD91 function at the cell membrane and regulate uptake of C1q-opsonised apoptotic cells. Our results show that Btk directly phosphorylates CRT and that in the absence of Btk, CRT fails to localize with CD91 at the cell surface and at the phagocytic cup. Critically, a blocking Ab against CRT in wild-type macrophages mimics the inability of Btk-deficient macrophages to phagocytose apoptotic cells efficiently, indicating the critical importance of Btk in regulating CRT-driven apoptotic cell uptake. Our data have revealed a novel regulatory role for Btk in mediating apoptotic cell clearance, with CRT identified as the critical component of the CRT/CD91/C1q system targeted by Btk. Given the importance of clearing apoptotic cell debris to prevent inappropriate exposure of TLRs to endogenous ligands, our results have important implications regarding the role of Btk in myeloid cell function.

show abstract

The Rab11a GTPase Controls Toll-like Receptor 4-Induced Activation of Interferon Regulatory Factor-3 on Phagosomes

Cited by 178 publications

References 36 publications

MHC Class II Antigen Presentation by Dendritic Cells Regulated through Endosomal Sorting

MHC Class II Antigen Presentation by Dendritic Cells Regulated through Endosomal Sorting

CD14 dependence of TLR4 endocytosis and TRIF signaling displays ligand specificity and is dissociable in endotoxin tolerance

Bruton's Tyrosine Kinase Is Required for Apoptotic Cell Uptake via Regulating the Phosphorylation and Localization of Calreticulin

Contact Info

Product

Resources

About