title: Ras transformation results in cleavage of reticulon protein Nogo-B that is associated with impairment of IFN response.
abstract: Dysregulation of Ras signaling is the major cause of various cancers. Aberrant Ras signaling, however, provides a favorable environment for many viruses, making them suitable candidates as cancer-killing therapeutic agents. Susceptibility of cancer cells to such viruses is mainly due to impaired type I interferon (IFN) response, often as a result of activated Ras/ERK signaling in these cells. In this study, we searched for cellular factors modulated by Ras signaling and their potential involvement in promoting viral oncolysis. We found that upon Ras transformation of NIH-3T3 cells, the N-terminus of Nogo-B (reticulon 4) was proteolytically cleaved. Interestingly, Nogo knockdown (KD) in non-transformed and Ras-transformed cells both enhanced virus-induced IFN response, suggesting that both cleaved and uncleaved Nogo can suppress IFN response. However, pharmacological blockade of Nogo cleavage in Ras-transformed cells significantly enhanced virus-induced IFN response, suggesting that cleaved Nogo contributes to enhanced IFN suppression in these cells. We further showed that IFN suppression associated with Ras-induced Nogo-B cleavage was distinct from but synergistic with that associated with an activated Ras/ERK pathway. Our study therefore reveals an important and novel role of Nogo-B and its cleavage in the suppression of anti-viral immune responses by oncogenic Ras transformation.
authors.affiliation: a Department of Microbiology and Immunology ; Dalhousie University ; Halifax , Nova Scotia , Canada.
authors.forename: Dae-Gyun
authors.initials: DG
authors.lastname: Ahn
authors.forename: Tanveer
authors.initials: T
authors.lastname: Sharif
authors.forename: Kenneth
authors.initials: K
authors.lastname: Chisholm
authors.forename: Devanand M
authors.initials: DM
authors.lastname: Pinto
authors.forename: Shashi A
authors.initials: SA
authors.lastname: Gujar
authors.forename: Patrick W K
authors.initials: PW
authors.lastname: Lee
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D057809:HEK293 Cells; D006801:Humans; D007372:Interferons / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D051379:Mice; D041681:NIH 3T3 Cells; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C512615:Nogo-B receptor, mouse; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; D007372:Interferons; D018631:ras Proteins
keywords: Nogo; cleavage; interferon; reticulon 4B; transformed cells