Soluble PD-L1 generated by endogenous retroelement exaptation is a receptor antagonist
| Autor: | Spyros I. Papamichos, Kevin W. Ng, George R. Young, Eleonora Ottina, Jan Attig, George Kassiotis, Ioannis Kotsianidis |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Untranslated region retroelement B7-H1 Antigen Immunology and Inflammation 0302 clinical medicine Biology (General) Receptor Conserved Sequence Chemistry General Neuroscience Hominidae Biological activity Exons General Medicine Chromosomes and Gene Expression Receptor antagonist 3. Good health Cell biology Transmembrane domain medicine.anatomical_structure Regulatory sequence 030220 oncology & carcinogenesis Medicine Research Article Human PD-L1 Retroelements receptor antagonist QH301-705.5 medicine.drug_class Science T cell LINE General Biochemistry Genetics and Molecular Biology Evolution Molecular 03 medical and health sciences Protein Domains mental disorders medicine Animals Humans Gene Cell Proliferation Immunosuppression Therapy General Immunology and Microbiology Mice Inbred C57BL Alternative Splicing HEK293 Cells 030104 developmental biology Solubility |
| Zdroj: | eLife, Vol 8 (2019) eLife |
| ISSN: | 2050-084X |
| Popis: | Immune regulation is a finely balanced process of positive and negative signals. PD-L1 and its receptor PD-1 are critical regulators of autoimmune, antiviral and antitumoural T cell responses. Although the function of its predominant membrane-bound form is well established, the source and biological activity of soluble PD-L1 (sPD-L1) remain incompletely understood. Here, we show that sPD-L1 in human healthy tissues and tumours is produced by exaptation of an intronic LINE-2A (L2A) endogenous retroelement in the CD274 gene, encoding PD-L1, which causes omission of the transmembrane domain and the regulatory sequence in the canonical 3’ untranslated region. The alternatively spliced CD274-L2A transcript forms the major source of sPD-L1 and is highly conserved in hominids, but lost in mice and a few related species. Importantly, CD274-L2A-encoded sPD-L1 lacks measurable T cell inhibitory activity. Instead, it functions as a receptor antagonist, blocking the inhibitory activity of PD-L1 bound on cellular or exosomal membranes. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|