title: Regulatory effects of mammalian target of rapamycin-activated pathways in type I and II interferon signaling.
abstract: The mechanisms regulating initiation of mRNA translation for the generation of protein products that mediate interferon (IFN) responses are largely unknown. We have previously shown that both Type I and II IFNs engage the mammalian target of rapamycin (mTOR), resulting in downstream phosphorylation and deactivation of the translational repressor 4E-BP1 (eIF4E-binding protein 1). In the current study, we provide direct evidence that such regulation of 4E-BP1 by IFNalpha or IFNgamma results in sequential dissociation of 4E-BP1 from eukaryotic initiation factor-4E and subsequent formation of a functional complex between eukaryotic initiation factor-4E and eukaryotic initiation factor-4G, to allow initiation of mRNA translation. We also demonstrate that the induction of key IFNalpha- or IFNgamma-inducible proteins (ISG15 (interferon-stimulated gene 15) and CXCL10) that mediate IFN responses are enhanced in 4E-BP1 (4E-BP1(-/-)) knockout MEFs, as compared with wild-type 4E-BP1(+/+) MEFs. On the other hand, IFN-dependent transcriptional regulation of the Isg15 and Cxcl10 genes is intact in the absence of 4E-BP1, as determined by real time reverse transcriptase-PCR assays and promoter assays for ISRE and GAS, establishing that 4E-BP1 plays a selective negative regulatory role in IFN-induced mRNA translation. Interestingly, the induction of expression of ISG15 and CXCL10 proteins by IFNs was also strongly enhanced in cells lacking expression of the tuberin (TSC2(-/-)) or hamartin (TSC1(-/-)) genes, consistent with the known negative regulatory effect of the TSC1-TSC2 complex on mTOR activation. In other work, we demonstrate that the induction of an IFN-dependent antiviral response is strongly enhanced in cells lacking expression of 4E-BP1 and TSC2, demonstrating that these elements of the IFN-activated mTOR pathway exhibit important regulatory effects in the generation of IFN responses. Taken altogether, our data suggest an important role for mTOR-dependent pathways in IFN signaling and identify 4E-BP1 and TSC1-TSC2 as key components in the generation of IFN-dependent biological responses.
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Northwestern University Medical School and Lakeside Veterans Affairs Medical Center, Chicago, Illinois 60611, USA.
authors.forename: Surinder
authors.initials: S
authors.lastname: Kaur
authors.forename: Lakhvir
authors.initials: L
authors.lastname: Lal
authors.forename: Antonella
authors.initials: A
authors.lastname: Sassano
authors.forename: Beata
authors.initials: B
authors.lastname: Majchrzak-Kita
authors.forename: Maya
authors.initials: M
authors.lastname: Srikanth
authors.forename: Darren P
authors.initials: DP
authors.lastname: Baker
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Petroulakis
authors.forename: Nissim
authors.initials: N
authors.lastname: Hay
authors.forename: Nahum
authors.initials: N
authors.lastname: Sonenberg
authors.forename: Eleanor N
authors.initials: EN
authors.lastname: Fish
authors.forename: Leonidas C
authors.initials: LC
authors.lastname: Platanias
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D018797:Cell Cycle Proteins; D054357:Chemokine CXCL10; D019743:Chemokines, CXC / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007370:Interferon Type I / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism*; D051379:Mice; D010750:Phosphoproteins / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000998:Antiviral Agents; D018797:Cell Cycle Proteins; D054357:Chemokine CXCL10; D019743:Chemokines, CXC; C087000:EIF4EBP1 protein, human; D007370:Interferon Type I; D010750:Phosphoproteins; C000624650:TSC1 protein, human; C000624653:TSC2 protein, human; C000624651:Tsc1 protein, mouse; C000624654:Tsc2 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D007371:Interferon-gamma; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases