ABIN-2, of the TPL-2 Signaling Complex, Modulates Mammalian Inflammation

• Published in: Trends in immunology Vol. 40; no. 9; pp. 799 - 808
• Main Authors: Webb, Louise V., Ventura, Sonia, Ley, Steven C.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-09-2019; Elsevier Limited
• Subjects: Adaptor Proteins, Signal Transducing - immunology; Animals; Asthma; Bone marrow; Breast cancer; Colitis; Dendritic cells; Disease; Experiments; Extracellular signal-regulated kinase; Gene expression; Genetic engineering; Humans; Immune response; Immune system; Inflammation; Inflammation - immunology; Inflammatory bowel disease; Inflammatory diseases; Kinases; Lymphocytes; Mammals; MAP Kinase Kinase Kinases - deficiency; MAP Kinase Kinase Kinases - immunology; Metastasis; Mice; Mice, Knockout; Mutation; Ovarian cancer; Phase transitions; Phenotypes; Prostate; Protein expression; Proteins; Proto-Oncogene Proteins - deficiency; Proto-Oncogene Proteins - immunology; Receptor mechanisms; Respiratory tract; Respiratory tract diseases; Signal Transduction - immunology; Toll-like receptors; Tumor necrosis factor-TNF; Tumorigenesis; Ubiquitin
• ISSN: 1471-4906; 1471-4981
• DOI: 10.1016/j.it.2019.07.001

Mammalian TPL-2 kinase (MAP3K8) mediates Toll-like receptor activation of ERK1/2 and p38α MAP kinases and is critical for regulating immune responses to pathogens. TPL-2 also has an important adaptor function, maintaining stability of associated ABIN-2 ubiquitin-binding protein. Consequently, phenotypes detected in Map3k8–/– mice can be caused by lack of TPL-2, ABIN-2, or both proteins. Recent studies show that increased inflammation of Map3k8–/– mice in allergic airway inflammation and colitis results from reduced ABIN-2 signaling, rather than blocked TPL-2 signaling. However, Map3k8–/– mice have been employed extensively to evaluate the potential of TPL-2 as an anti-inflammatory drug target. We posit that Map3k8D270A/D270A mice, expressing catalytically inactive TPL-2 and physiologic ABIN-2, should be used to evaluate the potential effects of TPL-2 inhibitors in disease.
TPL-2 (MAP3K8) is a MAP 3-kinase that activates the ERK1/2 and p38α MAP kinases in mammalian myeloid cells following TLR and TNFR1 stimulation. The use of Map3k8–/– mice to investigate the role of TPL-2 kinase in inflammatory diseases is unreliable due to the confounding loss of the associated ubiquitin-binding protein ABIN-2.The severe house dust mite-induced (HDM) airway allergic inflammation observed in Map3k8–/– mice results from reduced ABIN-2/A20 interactions and is not a consequence of a block in TPL-2 signaling. Hence, small molecule inhibition of TPL-2 may not exacerbate allergy in atopic individuals.The increased susceptibility of Map3k8–/– mice to DSS-colitis may be due to reduced ABIN-2 ubiquitin binding in a manner that is independent from the absence of TPL-2 signaling activity.Current evidence in mice suggests that TPL-2 signaling may be proinflammatory, while ABIN-2 signaling appears to have an opposing anti-inflammatory function.