Lysosomal trafficking regulator Lyst links membrane trafficking to toll-like receptor–mediated inflammatory responses

Westphal, Andreas; Cheng, Weijia; Yu, Jinbo; Grassl, Guntram A.; Krautkrämer, Martina; Holst, Otto; Föger, Niko; Lee, Kyeong-Hee

doi:10.1084/jem.20141461

Cited by 43 publications

(56 citation statements)

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“…The latter study also suggested that the large size of the granules in LYST‐deficient NK cells impeded their secretion through the cortical actin network at the immunological synapse, and that granule secretion in these cells was normalized by actin depolymerization . LYST also plays a role in phagolysosomal maturation, resulting in defective TRIF/TRAM‐dependent signaling by toll‐like receptors 3 and 4 in LYST‐deficient macrophages and dendritic cells and consequent impaired innate immune responses to bacterial pathogens . Similarly, the D melanogaster LYST orthologue prevents fusion of incompletely matured phagosomes .…”

Section: Additional Disorders Of Lro Biogenesis Secretion and Motilitymentioning

confidence: 94%

“…Surviving patients suffer from a late‐onset neurological impairment . The symptoms reflect defects in lysosome and phagosome maturation, concomitant with the formation of giant enlarged lysosomes and LROs that cannot be secreted . The defective gene, LYST or CHS1, encodes a ~4000 amino acid protein with several identifiable protein domains including BEACH, pleckstrin homology, WD40 repeats, perilipin‐like, lectin‐like and HEAT/Armadillo‐like repeats .…”

Section: Additional Disorders Of Lro Biogenesis Secretion and Motilitymentioning

confidence: 99%

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The road to lysosome‐related organelles: Insights from Hermansky‐Pudlak syndrome and other rare diseases

Bowman

Bi‐Karchin

et al. 2019

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Lysosome-related organelles (LROs) comprise a diverse group of cell type-specific, membrane-bound subcellular organelles that derive at least in part from the endolysosomal system but that have unique contents, morphologies and functions to support specific physiological roles. They include: melanosomes that provide pigment to our eyes and skin; alpha and dense granules in platelets, and lytic granules in cytotoxic T cells and natural killer cells, which release effectors to regulate hemostasis and immunity; and distinct classes of lamellar bodies in lung epithelial cells and keratinocytes that support lung plasticity and skin lubrication. The formation, maturation and/or secretion of subsets of LROs are dysfunctional or entirely absent in a number of hereditary syndromic disorders, including in particular the Hermansky-Pudlak syndromes. This review provides a comprehensive overview of LROs in humans and model organisms and presents our current understanding of how the products of genes that are defective in heritable diseases impact their formation, motility and ultimate secretion.

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Section: Additional Disorders Of Lro Biogenesis Secretion and Motilitymentioning

confidence: 94%

Section: Additional Disorders Of Lro Biogenesis Secretion and Motilitymentioning

confidence: 99%

The road to lysosome‐related organelles: Insights from Hermansky‐Pudlak syndrome and other rare diseases

Bowman

Bi‐Karchin

et al. 2019

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“…Confocal images taken after a 6-hour stimulation at MOI 10:1 showed that both WT and MyD88−/− BMDMs contained degraded GFP+ Bb within the cell actin matrix ( Figure 4A and 4B ). To assess phagosome maturation, we quantitated recruitment of LAMP-1 to Bb-containing phagosomes by looking at colocalization of LAMP-1 and GFP fluorescence intensity (55). Both WT and MyD88−/− BMDMs showed comparable LAMP-1 and Bb colocalization in phagosomes ( Figure 4A and 4B , graphs).…”

Section: Resultsmentioning

confidence: 99%

Macrophage mediated recognition and clearance ofBorrelia burgdorferinelicits MyD88-dependent and -independent phagosomal signals that contribute to phagocytosis and inflammation

Benjamin¹,

Hawley²,

Vera-Licona³

et al. 2019

Preprint

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35Lyme disease is a tick-borne illness caused by the spirochete Borrelia burgdorferi (Bb). It 36 is believed that the robust inflammatory response induced by the host's innate immune 37 system is responsible for the clinical manifestations associated with Bb infection. The 38 macrophage plays a central role in the immune response to many bacterial infections and 39 is thought to play a central role in activation of the innate immune response to Bb. 40 Previous studies have shown that following phagocytosis of spirochetes by macrophages, 41 phagosome maturation results in degradation of Bb and liberation of bacterial lipoproteins 42 and nucleic acids, which are recognized by TLR2 and TLR8, respectively, and elicit 43MyD88-mediated phagosome signaling cascades. Bone marrow-derived macrophages 44 (BMDMs) from MyD88 -/mice show significantly reduced spirochete uptake and 45 inflammatory cytokine production when incubated with Bb ex vivo. Paradoxically, 46additional studies revealed that Bb-infected MyD88 -/mice exhibit inflammation in joint 47 and heart tissues. To determine the contribution of MyD88 to macrophage-mediated 48 spirochete clearance, we compared wildtype (WT) and MyD88 -/mice using a murine 49 model of Lyme disease. MyD88 -/mice showed increased Bb burdens in hearts 28 days 50 post infection, while H&E staining and immunohistochemistry showed significantly 51 increased inflammation and greater macrophage infiltrate in the hearts of MyD88 -/mice. 52This suggests that Bb triggers MyD88-independent inflammatory pathways in 53 macrophages to facilitate cell recruitment to tissues. Upon stimulation with Bb ex vivo, 54WT and MyD88 -/-BMDMs exhibit significant differences in bacteria uptake, suggesting 55 that MyD88 signaling mediates cytoskeleton remodeling and the formation of membrane 56 protrusions to enhance bacteria phagocytosis. A comprehensive transcriptome 57 comparison in Bb-infected WT and MyD88 -/-BMDMs identified a large cohort of MyD88-58 dependent genes that are differentially expressed in response to Bb, including genes 59 involved in actin and cytoskeleton organization (Daam1, Fmnl1). We also identified a 60 cohort of differentially-expressed MyD88-independent chemokines (Cxcl2, Ccl9) known 61 to recruit macrophages. We identified master regulators and generated networks which 62 model potential signaling pathways that mediate both phagocytosis and the inflammatory 63 AUTHOR SUMMARY 67Macrophages play prominent roles in bacteria recognition and clearance, including 68Borrelia burgdorferi (Bb), the Lyme disease spirochete. To elucidate mechanisms by 69 which MyD88/TLR signaling enhances clearance of Bb by macrophages, we studied Bb-70 infected wildtype (WT) and MyD88-/-mice and Bb-stimulated bone marrow-derived 71 macrophages (BMDMs). Bb-infected MyD88-/-mice show increased bacterial burdens, 72 macrophage infiltration and altered gene expression in inflamed heart tissue. MyD88-/-73 BMDMs exhibit impaired uptake of spirochetes but comparable maturation of 74 phagosomes following internaliza...

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“…The LYST protein interacts with some cytoplasmic proteins that play an important role in vesicular transport regulation signal transduction [3] that leads to a decreased phagocytosis, which results in recurrent pyogenic infections, partial albinism and peripheral neuropathy. The idea that toll-like receptor (TLR) signaling and function can be controlled by the regulation of the endosomal trafficking network has been explored [5] and the results demonstrated that LYST protein selectively controls TLR3-and TLR4-mediated proinflammatory responses. Mechanistic in vitro studies revealed that Lyst regulates phagosomal trafficking/ maturation upon microbial encounter and specifically affects TRIF/IRF3 (IFN regulatory factor 3)-mediated endosomal TLR signaling.…”

Section: Introductionmentioning

confidence: 99%

“…In vivo, loss of functional Lyst results in impaired immune responses against infection and prevents uncontrolled inflammation during septic shock. The identification of Lyst as a physiological regulator of TLR function reveals how the regulation of the cellular membrane trafficking network can affect specific immune receptor signaling pathways and inflammatory responses [5]. The association between CHS and infection by human immunodeficiency virus type 1 (HIV-1) is rare.…”

Section: Introductionmentioning

confidence: 99%

Association of Chediak-Higashi Syndrome and Human Immunodeficiency Virus Type 1 Acute Infection

Bernarchi¹,

Gehring²,

Ruzon³

et al. 2017

J Transm Dis Immun

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Context: The Chediak-Higashi syndrome (CHS) is a rare autosomal and recessive disease associated with a genetic alteration of the lysosomal trafficking regulator (LYST) gene (CHS1/LYST). The LYST protein interacts with some cytoplasmic proteins that play an important role in vesicular transport regulation signal transduction that leads to a decreased phagocytosis, which results in recurrent pyogenic infections, partial albinism and peripheral neuropathy. The association between CHS and infection by human immunodeficiency virus type 1 (HIV-1) is rare. The aim of this study is to report the case of a patient with CHS and had incidental diagnosis of acute HIV-1 infection during hospitalization for treatment of a urological disorder.Case Report: An 18-year-old male with CHS presented a penile injury with a large foreskin lesion and areas of necrosis, bleeding, and fetid smelling. He reported risk factors associated with the transmission of HIV infection that was confirmed using serological and molecular tests. Although he had abandoned the combined antiretroviral therapy started after the HIV-1 infection diagnosis, the laboratory tests performed for monitoring the HIV-1 infection during the two-year follow-up showed no significant decline in the CD4 + T cell counts and no significant changes in the viral load.Conclusions: This case report emphasizes that patients with CHS are equally susceptible to HIV-1 infection; nonetheless, they may show slower viral replication and immune deterioration than individuals without CHS, which results in a slower clinical course of HIV-1 infection.

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Lysosomal trafficking regulator Lyst links membrane trafficking to toll-like receptor–mediated inflammatory responses

Abstract: Westphal et al. demonstrate a role of lysosomal trafficking regulator Lyst that couples the regulation of endolysosomal trafficking to inflammatory responses by the control of toll-like receptor–mediated endosomal TRIF signaling pathways.

Cited by 43 publications

References 50 publications

The road to lysosome‐related organelles: Insights from Hermansky‐Pudlak syndrome and other rare diseases

The road to lysosome‐related organelles: Insights from Hermansky‐Pudlak syndrome and other rare diseases

Macrophage mediated recognition and clearance ofBorrelia burgdorferinelicits MyD88-dependent and -independent phagosomal signals that contribute to phagocytosis and inflammation

Association of Chediak-Higashi Syndrome and Human Immunodeficiency Virus Type 1 Acute Infection

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