Retromer Promotes Immune Quiescence by Suppressing Spätzle‐Toll Pathway in <i>Drosophila</i>

Zhou, Bo; Yun, Eun‐Young; Ray, Lorraine; You, Jia; Ip, Y. Tony; Lin, Xinhua

doi:10.1002/jcp.24472

Cited by 9 publications

(11 citation statements)

References 36 publications

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“…Inappropriate activation of inflammatory responses or lack of immune signaling lead to serious conditions such as inflammatory diseases or immunodeficiency, respectively. Recent studies reveal that innate immunity is regulated by multiple factors, including sumoylation and the retromer complex, which fine tune immune activity (32,33). The present study clearly showed that glycosylation plays an important role in maintaining innate immune homeostasis and activation of immune responses.…”

Section: Discussionsupporting

confidence: 63%

Dynamic regulation of innate immune responses in Drosophila by Senju-mediated glycosylation

Yamamoto-Hino

Muraoka

Kondo

et al. 2015

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

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The innate immune system is the first line of defense encountered by invading pathogens. Delayed and/or inadequate innate immune responses can result in failure to combat pathogens, whereas excessive and/or inappropriate responses cause runaway inflammation. Therefore, immune responses are tightly regulated from initiation to resolution and are repressed during the steady state. It is well known that glycans presented on pathogens play important roles in pathogen recognition and the interactions between host molecules and microbes; however, the function of glycans of host organisms in innate immune responses is less well known. Here, we show that innate immune quiescence and strength of the immune response are controlled by host glycosylation involving a novel UDPgalactose transporter called Senju. In senju mutants, reduced expression of galactose-containing glycans resulted in hyperactivation of the Toll signaling pathway in the absence of immune challenges. Genetic epistasis and biochemical analyses revealed that Senju regulates the Toll signaling pathway at a step that converts Toll ligand Spatzle to its active form. Interestingly, Toll activation in immune-challenged wild type (WT) flies reduced the expression of galactose-containing glycans. Suppression of the degalactosylation by senju overexpression resulted in reduced induction of Toll-dependent expression of an antimicrobial peptide, Drosomycin, and increased susceptibility to infection with Gram-positive bacteria. These data suggest that Senju-mediated galactosylation suppresses undesirable Toll signaling activation during the steady state; however, Toll activation in response to infection leads to degalactosylation, which raises the immune response to an adequate level and contributes to the prompt elimination of pathogens.innate immunity | glycosylation | Toll pathway | nucleotide sugar transporter | galactose

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Section: Discussionsupporting

confidence: 63%

Dynamic regulation of innate immune responses in Drosophila by Senju-mediated glycosylation

Yamamoto-Hino

Muraoka

Kondo

et al. 2015

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

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“…dOCRL-TagRFPT localized to discrete puncta at the hemocyte plasma membrane and throughout the cytoplasm ( Fig 3A ). These puncta colocalized most strongly with He-Gal4-driven GFP tagged clathrin light chain (Clc), and moderately colocalized with other compartment markers ( Fig 3B , S4A Fig ), including endogenously tagged YFP-Rab5 (early endosomes), YFP-Rab7 (late endosomes), YFP-Rab11 (recycling endosomes), and He-GAL4-driven Vps35-GFP (a component of the endosomal cargo-sorting retromer complex, which has itself previously been implicated in restricting innate immune activation [ 18 , 22 ]). Interestingly, dOCRL exhibited a qualitatively different pattern of association with different compartments.…”

Section: Resultsmentioning

confidence: 99%

“…In Drosophila , the innate immune system is poised to respond quickly and effectively to infection. Mutants in a variety of components of the endosomal trafficking system exhibit various features of immune activation, including increased hemocyte abundance [ 18 – 22 ], but it has remained unclear which specific immune tissues or pathways are altered or how this leads to hemocyte activation. Here we show that dOCRL controls endosomal traffic in Drosophila larval hemocytes to autonomously restrict immune cell activation.…”

Section: Introductionmentioning

confidence: 99%

dOCRL maintains immune cell quiescence by regulating endosomal traffic

et al. 2017

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Lowe Syndrome is a developmental disorder characterized by eye, kidney, and neurological pathologies, and is caused by mutations in the phosphatidylinositol-5-phosphatase OCRL. OCRL plays diverse roles in endocytic and endolysosomal trafficking, cytokinesis, and ciliogenesis, but it is unclear which of these cellular functions underlie specific patient symptoms. Here, we show that mutation of Drosophila OCRL causes cell-autonomous activation of hemocytes, which are macrophage-like cells of the innate immune system. Among many cell biological defects that we identified in docrl mutant hemocytes, we pinpointed the cause of innate immune cell activation to reduced Rab11-dependent recycling traffic and concomitantly increased Rab7-dependent late endosome traffic. Loss of docrl amplifies multiple immune-relevant signals, including Toll, Jun kinase, and STAT, and leads to Rab11-sensitive mis-sorting and excessive secretion of the Toll ligand Spåtzle. Thus, docrl regulation of endosomal traffic maintains hemocytes in a poised, but quiescent state, suggesting mechanisms by which endosomal misregulation of signaling may contribute to symptoms of Lowe syndrome.

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“…Alternatively, distinct SNX-BAR proteins control a currently not well-defined Retro-2-sensitive retrograde trafficking pathway that delivers distinct nutrients to the bacteria or alternatively could be related to factors controlling innate immunity. The idea of an innate immunity-related function of the retromer is further supported by the recently published observation in Drosophila that retromer can also control the Toll pathway [ 51 ].…”

Section: Discussionmentioning

confidence: 99%

The Proteome of the Isolated Chlamydia trachomatis Containing Vacuole Reveals a Complex Trafficking Platform Enriched for Retromer Components

et al. 2015

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Chlamydia trachomatis is an important human pathogen that replicates inside the infected host cell in a unique vacuole, the inclusion. The formation of this intracellular bacterial niche is essential for productive Chlamydia infections. Despite its importance for Chlamydia biology, a holistic view on the protein composition of the inclusion, including its membrane, is currently missing. Here we describe the host cell-derived proteome of isolated C. trachomatis inclusions by quantitative proteomics. Computational analysis indicated that the inclusion is a complex intracellular trafficking platform that interacts with host cells’ antero- and retrograde trafficking pathways. Furthermore, the inclusion is highly enriched for sorting nexins of the SNX-BAR retromer, a complex essential for retrograde trafficking. Functional studies showed that in particular, SNX5 controls the C. trachomatis infection and that retrograde trafficking is essential for infectious progeny formation. In summary, these findings suggest that C. trachomatis hijacks retrograde pathways for effective infection.

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Retromer Promotes Immune Quiescence by Suppressing Spätzle‐Toll Pathway in Drosophila

Cited by 9 publications

References 36 publications

Dynamic regulation of innate immune responses in Drosophila by Senju-mediated glycosylation

Dynamic regulation of innate immune responses in Drosophila by Senju-mediated glycosylation

dOCRL maintains immune cell quiescence by regulating endosomal traffic

The Proteome of the Isolated Chlamydia trachomatis Containing Vacuole Reveals a Complex Trafficking Platform Enriched for Retromer Components

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