A high-coverage shRNA screen identifies TMEM129 as an E3 ligase involved in ER-associated protein degradation
| Autor: | Michael T. McManus, Jonathan S. Weissman, Cornelia M Voorburg, Weronika Patena, Robert Jan Lebbink, Emily M LeProust, Maaike E. Ressing, Michael L. van de Weijer, Rutger D. Luteijn, Emmanuel J. H. J. Wiertz, Hanneke Hoelen, Siyuan Chen, Elisabeth Kremmer, Rob C. Hoeben, Mirjam A M Lohuis, Michael C. Bassik |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Protein Folding
Ubiquitin-Protein Ligases Cytomegalovirus Down-Regulation General Physics and Astronomy Human leukocyte antigen Endoplasmic-reticulum-associated protein degradation Ubiquitin-conjugating enzyme Protein degradation Endoplasmic Reticulum Article General Biochemistry Genetics and Molecular Biology Small hairpin RNA Viral Proteins 03 medical and health sciences 0302 clinical medicine Cell Line Tumor Ring finger medicine Humans Clustered Regularly Interspaced Short Palindromic Repeats RNA Small Interfering Nuclear protein Selenoproteins 030304 developmental biology Adenosine Triphosphatases 0303 health sciences Multidisciplinary biology Histocompatibility Antigens Class I Membrane Proteins Nuclear Proteins Proteins RNA-Binding Proteins Endoplasmic Reticulum-Associated Degradation U937 Cells General Chemistry Molecular biology Ubiquitin ligase Cell biology HEK293 Cells medicine.anatomical_structure Cytomegalovirus Infections Ubiquitin-Conjugating Enzymes biology.protein RNA Interference 030217 neurology & neurosurgery |
| Zdroj: | Nature Communications, 5 Nat. Commun. 5:3832 (2014) Nature Communications |
| Popis: | Misfolded ER proteins are retrotranslocated into the cytosol for degradation via the ubiquitin–proteasome system. The human cytomegalovirus protein US11 exploits this ER-associated protein degradation (ERAD) pathway to downregulate HLA class I molecules in virus-infected cells, thereby evading elimination by cytotoxic T-lymphocytes. US11-mediated degradation of HLA class I has been instrumental in the identification of key components of mammalian ERAD, including Derlin-1, p97, VIMP and SEL1L. Despite this, the process governing retrotranslocation of the substrate is still poorly understood. Here using a high-coverage genome-wide shRNA library, we identify the uncharacterized protein TMEM129 and the ubiquitin-conjugating E2 enzyme UBE2J2 to be essential for US11-mediated HLA class I downregulation. TMEM129 is an unconventional C4C4-type RING finger E3 ubiquitin ligase that resides within a complex containing various other ERAD components, including Derlin-1, Derlin-2, VIMP and p97, indicating that TMEM129 is an integral part of the ER-resident dislocation complex mediating US11-induced HLA class I degradation. The human cytomegalovirus protein US11 downregulates host immune responses by redirecting HLA class I molecules for endoplasmic reticulum-associated protein degradation. Using a high-coverage genome-wide shRNA screen, the authors identify TMEM129 as an E3 ubiquitin ligase essential for this process. |
| Databáze: | OpenAIRE |
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