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Evidence of ERV activity has been observed widely in both health and disease. While this is most often cited as a bystander effect of cell culture or disease states, it is unclear which signals control ERV transcription. Bioinformatic analysis suggests that the viral promoter of endogenous retrovirus K (ERVK) is responsive to inflammatory transcription factors. Here we show that one reason for ERVK upregulation in amyotrophic lateral sclerosis (ALS) is the presence of functional interferon-stimulated response elements (ISREs) in the viral promoter. Transcription factor overexpression assays revealed independent and synergistic upregulation of ERVK by interferon regulatory factor 1 (IRF1) and NF-\u03baB isoforms. Tumor necrosis factor alpha (TNF-\u03b1) and LIGHT cytokine treatments of human astrocytes and neurons enhanced ERVK transcription and protein levels through IRF1 and NF-\u03baB binding to the ISREs. We further show that in ALS brain tissue, neuronal ERVK reactivation is associated with the nuclear translocation of IRF1 and NF-\u03baB isoforms p50 and p65. ERVK overexpression can cause motor neuron pathology in murine models. Our results implicate neuroinflammation as a key trigger of ERVK provirus reactivation in ALS. These molecular mechanisms may also extend to the pathobiology of other ERVK-associated inflammatory diseases, such as cancers, HIV infection, rheumatoid arthritis, and schizophrenia.<\/jats:p>\n                  <jats:p>\n                    <jats:bold>IMPORTANCE<\/jats:bold>\n                    It has been well established that inflammatory signaling pathways in ALS converge at NF-\u03baB to promote neuronal damage. Our findings suggest that inflammation-driven IRF1 and NF-\u03baB activity promotes ERVK reactivation in neurons of the motor cortex in ALS. Thus, quenching ERVK activity through antiretroviral or immunomodulatory regimens may hinder virus-mediated neuropathology and improve the symptoms of ALS or other ERVK-associated diseases.\n                  <\/jats:p>","DOI":"10.1128\/jvi.01503-16","type":"journal-article","created":{"date-parts":[[2016,8,10]],"date-time":"2016-08-10T22:48:46Z","timestamp":1470869326000},"page":"9338-9349","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":118,"title":["NF-\u03baB and IRF1 Induce Endogenous Retrovirus K Expression via Interferon-Stimulated Response Elements in Its 5\u2032 Long Terminal Repeat"],"prefix":"10.1128","volume":"90","author":[{"given":"Mamneet","family":"Manghera","sequence":"first","affiliation":[{"name":"Department of Biology, University of Winnipeg, Winnipeg, Manitoba, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Ferguson-Parry","sequence":"additional","affiliation":[{"name":"Department of Biology, University of Winnipeg, Winnipeg, Manitoba, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rongtuan","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Experimental Medicine, McGill University, Montr\u00e9al, Qu\u00e9bec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ren\u00e9e N.","family":"Douville","sequence":"additional","affiliation":[{"name":"Department of Biology, University of Winnipeg, Winnipeg, Manitoba, Canada"},{"name":"Department of Immunology, University of Manitoba, Winnipeg, Manitoba, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1186\/1742-4690-10-16"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1089\/107999002753452638"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20010753"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1111\/imr.12065"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2249.2010.04110.x"},{"key":"e_1_3_2_7_2","first-page":"637","article-title":"In vitro modulation of the multiple sclerosis (MS)-associated retrovirus by cytokines: implications for MS pathogenesis","volume":"9","author":"Serra C","year":"2003","unstructured":"Serra C, Mameli G, Arru G, Sotgiu S, Rosati G, Dolei A. 2003. 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