TRIM2, a novel member of the antiviral family, limits New World arenavirus entry.

Abstract

Tripartite motif (TRIM) proteins belong to a large family with many roles in host biology, including restricting virus infection. Here, we found that TRIM2, which has been implicated in cases of Charcot-Marie-Tooth disease (CMTD) in humans, acts by blocking hemorrhagic fever New World arenavirus (NWA) entry into cells. We show that Trim2-knockout mice, as well as primary fibroblasts from a CMTD patient with mutations in TRIM2, are more highly infected by the NWAs Junín and Tacaribe virus than wild-type mice or cells are. Using mice with different Trim2 gene deletions and TRIM2 mutant constructs, we demonstrate that its antiviral activity is uniquely independent of the RING domain encoding ubiquitin ligase activity. Finally, we show that one member of the TRIM2 interactome, signal regulatory protein α (SIRPA), a known inhibitor of phagocytosis, also restricts NWA infection and conversely that TRIM2 limits phagocytosis of apoptotic cells. In addition to demonstrating a novel antiviral mechanism for TRIM proteins, these studies suggest that the NWA entry and phagocytosis pathways overlap.

• Authors: Nicolas Sarute, Nouhou Ibrahim, Bani Medegan Fagla, Madakasira Lavanya, Christian Cuevas, Spyridon Stavrou, Guliz Otkiran-Clare, Henna Tyynismaa, Jorge Henao-Mejia, Susan R Ross
• Journal: PLoS biology (PLoS Biol) Vol. 17 Issue 2 Pg. e3000137 (02 2019) ISSN: 1545-7885 [Electronic] United States
• PMID: 30726215 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, Differentiation
• NARF protein, human
• Neurofilament Proteins
• Nuclear Proteins
• Receptors, Immunologic
• SIRPA protein, human
• neurofilament protein L
• MAPK1 protein, human
• MAPK3 protein, human
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3

Topics

• Animals
• Antigens, Differentiation (genetics, immunology, metabolism)
• Apoptosis
• Arenaviruses, New World (genetics, growth & development, pathogenicity)
• Brain (immunology, metabolism, virology)
• Cell Line, Tumor
• Charcot-Marie-Tooth Disease (genetics, metabolism, pathology)
• Chlorocebus aethiops
• Fibroblasts (immunology, metabolism, virology)
• Gene Expression Regulation
• HEK293 Cells
• Host-Pathogen Interactions (genetics, immunology)
• Humans
• Macrophages (immunology, metabolism, virology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mitogen-Activated Protein Kinase 1 (genetics, immunology, metabolism)
• Mitogen-Activated Protein Kinase 3 (genetics, immunology, metabolism)
• Neurofilament Proteins (genetics, immunology, metabolism)
• Nuclear Proteins (genetics, immunology, metabolism)
• Osteoblasts (immunology, metabolism, virology)
• Primary Cell Culture
• Receptors, Immunologic (genetics, immunology, metabolism)
• Signal Transduction
• Vero Cells
• Virus Internalization