The E3 Ubiquitin Ligase TMEM129 Is a Tri-Spanning Transmembrane Protein

Weijer, Michael L. van de; Muijlwijk, Guus H. van; Visser, Lenneke de; Costa, Ana I.; Wiertz, Emmanuel J. H. J.; Lebbink, Robert Jan

doi:10.3390/v8110309

Cited by 7 publications

(5 citation statements)

References 64 publications

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“…The PCR amplicon was cloned in a BIC-PGK-Zeo-T2a-mAmetrine;EF1A construct by Gibson assembly (NEB) according to the manufacturer’s instructions. The langerin-encoding vector and an empty vector (EV) control were introduced into THP1 cells by lentiviral transduction, as described by van de Weijer et al (58). In short, lentivirus was produced by HEK293T cells (CRL-3216; ATCC) in 24-well plates using standard lentiviral production protocols and third-generation packaging vectors.…”

Section: Methodsmentioning

confidence: 99%

Langerhans Cells Sense Staphylococcus aureus Wall Teichoic Acid through Langerin To Induce Inflammatory Responses

Dalen

Diaz

Rumpret

et al. 2019

mBio

100

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Staphylococcus aureus is a major cause of skin and soft tissue infections and aggravator of the inflammatory skin disease atopic dermatitis (AD [eczema]). Epicutaneous exposure to S. aureus induces Th17 responses through skin Langerhans cells (LCs), which paradoxically contribute to host defense but also to AD pathogenesis. The molecular mechanisms underlying the interaction between S. aureus and LCs are poorly understood. Here we demonstrate that human LCs directly interact with S. aureus through the pattern recognition receptor langerin (CD207). Human, but not mouse, langerin interacts with S. aureus through the conserved β-N-acetylglucosamine (GlcNAc) modifications on wall teichoic acid (WTA), thereby discriminating S. aureus from other staphylococcal species. Importantly, the specific S. aureus WTA glycoprofile strongly influences the level of proinflammatory cytokines that are produced by in vitro-generated LCs. Finally, in a murine epicutaneous infection model, S. aureus strongly upregulated transcripts of Cxcl1, Il6, and Il17, which required the presence of both human langerin and WTA β-GlcNAc. Our findings provide molecular insight into the unique proinflammatory capacities of S. aureus in relation to skin inflammation. IMPORTANCE The bacterium Staphylococcus aureus is an important cause of skin infections and is also associated with the occurrence and severity of eczema. Langerhans cells (LCs), a specific subset of skin immune cells, participate in the immune response to S. aureus, but it is yet unclear how LCs recognize S. aureus. Therefore, we investigated the molecular mechanism underlying the interaction between LCs and S. aureus. We identified that wall teichoic acid, an abundant polymer on the S. aureus surface, is recognized by langerin, a receptor unique to LCs. This interaction allows LCs to discriminate S. aureus from other related staphylococcal species and initiates a proinflammatory response similar to that observed in patients with eczema. Our data therefore provide important new insights into the relationship between S. aureus, LCs, and eczema.

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Section: Methodsmentioning

confidence: 99%

Langerhans Cells Sense Staphylococcus aureus Wall Teichoic Acid through Langerin To Induce Inflammatory Responses

Dalen

Diaz

Rumpret

et al. 2019

mBio

100

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“…Cells were then incubated for 30 min at 4°C with the conjugated antibody in icecold PBS + 0.5% saponin + 2% FCS and after two subsequent washing steps fixed with icecold 3.7% PFA in PBA and subjected to flow cytometry analysis (BD FACS Canto II). The antibody used was: PE-conjugated W6/32 (Serotec MCA81PE, 1:5) [11].…”

Section: Methodsmentioning

confidence: 99%

“…Cells were then incubated for 30 min at 4°C with the directly-conjugated antibody and after two subsequent washing steps fixed with icecold 3.7% PFA in PBA and subjected to flow cytometry analysis (BD FACS Canto II). The antibodies used were: PE-conjugated W6/32 (Serotec MCA81PE, 1:10) [11], anti-CD9-FITC (BD Pharmingen 555371, 1:40), anti-CD46-FITC (BD Pharmingen 555949, 1:20), anti-CD49b-PE (BD Pharmingen 555669, 1:20), anti-CD58-PE (BD Pharmingen 555921, 1:30), anti-CDw119-PE (BD Pharmingen 558934, 1:20).…”

Section: Surface Stainingmentioning

confidence: 99%

The SARS-CoV-2 accessory factor ORF7a downregulates MHC class I surface expression

Zheng¹,

Buhr²,

Praest³

et al. 2022

Preprint

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The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in over 500 million infections and more than six million deaths worldwide. Although the viral genomes of SARS-CoV-1 and SARS-CoV-2 share high sequence homology, the clinical and pathological features of COVID-19 differ profoundly from those of SARS. It is apparent that changes in viral genes contribute to the increased transmissibility of SARS-CoV-2 and pathology of COVID-19. Cytotoxic T lymphocytes play a key role in the elimination of virus-infected cells, mediated by recognition of virus-derived peptides that are presented on MHC class I molecules. Here, we show that SARS-CoV-2 can interfere with antigen presentation thereby evading immune surveillance. SARS-CoV-2 infection of monkey and human cell lines resulted in reduced cell-surface expression of MHC class I molecules. We identified a single viral gene product, the accessory factor open reading frame 7a (ORF7a), that mediates this effect. ORF7a interacts with HLA class I molecules in the ER, resulting in ER retention or impaired HLA heavy chain (HC) trafficking to the Golgi. Ultimately, these actions result in reduced HLA class I surface expression on infected cells. Whereas ORF7a from SARS-CoV-2 reduces surface HLA class I levels, the homologous ORF7a from the 2002 pandemic SARS-CoV-1 did not, suggesting that SARS-CoV-2 ORF7a acquired the ability to downregulate HLA-I during evolution of the virus. We identified a single amino acid in the SARS-CoV-1 ORF7a luminal domain that, upon mutating to the corresponding SARS-CoV-2 ORF7a sequence, induced a gain-of-function in HLA surface downregulation. By abrogating HLA class I antigen presentation via ORF7a, SARS-CoV-2 may evade host immune responses by inhibiting anti-viral cytotoxic T cell activity, thereby contributing to the pathology of COVID-19.

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“…The genes that overlapped with the CNVR private to breeds were not signi cantly enriched in biological processes, molecular functions and cellular components, while the ones that overlapped with the CNVR private to populations were signi cantly enriched (P ≤ 0.05) with such terms as aldosterone synthesis and secretion; glucagon signaling pathway; insulin secretion; glutamatergic synapse; thyroid hormone synthesis; gastric acid secretion and phosphatidylinositol signaling system. The most common CNVR (chr6:115,822,332-115,825,687) includes the gene TMEM129 (transmembrane protein 129) that has been reported to be responsible for ubiquitination and proteasome-mediated degradation of misformed or unassembled proteins in the cytosol [46][47][48], and belongs to a network responsible for cellular assembly and organization, cellular function and maintenance, and cell cycle [49].…”

Section: Functional Annotation and Gene Enrichment Analysismentioning

confidence: 99%

Detection of copy number variants in African goats using whole genome sequence data

Nandolo

Mészáros

Wurzinger

et al. 2020

Preprint

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Background Copy number variations (CNV) are a significant source of variation in the genome and are therefore essential to the understanding of genetic characterization. The aim of this study was to develop a fine-scaled copy number variation map for African goats. We used sequence data from multiple breeds and from multiple African countries. Results A total of 253,553 CNV (244,876 deletions and 8,677 duplications) were identified, corresponding to an overall average of 1,393 CNV per animal. The mean CNV length was 3.3 kb, with a median of 1.3 kb. There was substantial differentiation between the populations for some CNV, suggestive of the effect of population-specific selective pressures. A total of 6,231 global CNV regions (CNVR) were found across all animals, representing 59.2 Mb (2.4%) of the goat genome. About 1.6% of the CNVR were present in all 34 breeds and 28.7% were present in all 5 geographical areas across Africa, where animals had been sampled. The CNVR had genes that were highly enriched in important biological functions, molecular functions, and cellular components including retrograde endocannabinoid signaling, glutamatergic synapse and circadian entrainment. Conclusions This study presents the first fine CNV map of African goat based on WGS data and adds to the growing body of knowledge on the genetic characterization of goats.

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The E3 Ubiquitin Ligase TMEM129 Is a Tri-Spanning Transmembrane Protein

Cited by 7 publications

References 64 publications

Langerhans Cells Sense Staphylococcus aureus Wall Teichoic Acid through Langerin To Induce Inflammatory Responses

Langerhans Cells Sense Staphylococcus aureus Wall Teichoic Acid through Langerin To Induce Inflammatory Responses

The SARS-CoV-2 accessory factor ORF7a downregulates MHC class I surface expression

Detection of copy number variants in African goats using whole genome sequence data

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