NIK as a Druggable Mediator of Tissue Injury

• Published in: Trends in molecular medicine 2019-04, Vol.25 (4), p.341-360
• Main Authors: Valiño-Rivas, Lara, Vaquero, Juan José, Sucunza, David, Gutierrez, Sara, Sanz, Ana B., Fresno, Manuel, Ortiz, Alberto, Sanchez-Niño, Maria Dolores
• Format: Article
• Language: English
• Subjects: acute kidney injury; Animals; apoptosis; autoimmunity; Biomarkers; cell death; chronic kidney disease; cirrhosis; diabetes; epigenetic; esteatohepatitis; Gene Expression Regulation; hepatitis; Humans; Immunomodulation; inflammation; mantle lymphoma; MAP3K14; Mutation; myeloid leukemia; NF-kappaB-Inducing Kinase; NIK; osteoporosis; Protein Multimerization; Protein Processing, Post-Translational; Protein Serine-Threonine Kinases - chemistry; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - metabolism; Protein Stability; sarcopenia; Signal Transduction; TWEAK; verteporfin; Wounds and Injuries - etiology; Wounds and Injuries - metabolism; Wounds and Injuries - pathology
• ISSN: 1471-4914; 1471-499X
• DOI: 10.1016/j.molmed.2019.02.005

NF-κB-inducing kinase (NIK, MAP3K14) is best known as the apical kinase that triggers non-canonical NF-κB activation and by its role in the immune system. Recent data indicate a role for NIK expressed by non-lymphoid cells in cancer, kidney disease, liver injury, glucose homeostasis, osteosarcopenia, vascular calcification, hematopoiesis, and endothelial function. The spectrum of NIK-associated disease now ranges from immunodeficiency (when NIK is defective) to autoimmunity, cancer, sterile inflammation, fibrosis, and metabolic disease when NIK is overactive. The development of novel small-molecule NIK inhibitors has paved the way to test NIK targeting to treat disease in vivo, and may eventually lead to NIK targeting in the clinic. In addition, NIK activators are being explored for specific conditions such as myeloid leukemia. Both decreased protein degradation and increased mRNA levels can increase NIK protein levels and activity. NIK regulates the activation of transcription factors beyond NF-κB, as well as epigenetic modifications, mitochondrial dynamics, and others. Both NIK deficiency and NIK overactivity in lymphoid and non-lymphoid cells may cause disease: NIK deficiency causes immunodeficiency and contributes to myeloid leukemia; excess NIK activity favors autoimmunity, malignant cell growth, kidney injury, liver disease, glucose intolerance, osteosarcopenia, and complement-mediated endothelial injury; both deficient and excess NIK activity interfere with hematopoiesis. Small-molecule NIK inhibitors and LTβR-derived decoy peptides are in preclinical development for NIK overactivity; verteportin mimics NIK activation and may have activity against myeloid leukemia.