Mislocalization of the interferon inducible protein IFI16 by environmental insults: Implications in autoimmunity

Bawadekar, Mandar; Andrea, Marco De; Gariglio, Marisa; Landolfo, Santo

doi:10.1016/j.cytogfr.2014.10.003

Cited by 20 publications

(21 citation statements)

References 61 publications

(85 reference statements)

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“…A number of data also indicate the disease‐specific mislocalization of nuclear IFI16 in several inflammatory settings , while our group has recently demonstrated the occurrence of free IFI16 protein in the sera of autoimmune patients . Taken together, these observations suggest a role for IFI16 in inflammatory, detrimental cellular changes underlying autoimmune phenomena .…”

Section: Introductionsupporting

confidence: 52%

“…The IFI16 protein is overexpressed in several systemic autoimmune diseases and its specific autoantibodies are prevalent in the sera of these patients, thus linking this autoantigen to the pathogenesis of autoimmune diseases . A number of data also indicate the disease‐specific mislocalization of nuclear IFI16 in several inflammatory settings , while our group has recently demonstrated the occurrence of free IFI16 protein in the sera of autoimmune patients . Taken together, these observations suggest a role for IFI16 in inflammatory, detrimental cellular changes underlying autoimmune phenomena .…”

Section: Introductionmentioning

confidence: 52%

“…The nuclear phosphoprotein IFN‐inducible protein 16 (IFI16) is a member of the HIN‐200/Ifi‐200 gene family, whose overexpression drives early steps of an inflammatory response through NF‐κB–mediated secretion of proinflammatory molecules such as intercellular adhesion molecule 1, E‐selectin, interleukin‐8, and monocyte chemotactic protein 1 . The IFI16 protein is overexpressed in several systemic autoimmune diseases and its specific autoantibodies are prevalent in the sera of these patients, thus linking this autoantigen to the pathogenesis of autoimmune diseases .…”

Section: Introductionmentioning

confidence: 99%

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Circulating Interferon‐Inducible Protein IFI16 Correlates With Clinical and Serological Features in Rheumatoid Arthritis

Alunno

Caneparo

Bistoni

et al. 2016

Arthritis Care & Research

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Objective. The interferon-inducible protein 16 (IFI16) has been detected in sera from patients with autoimmune/ inflammatory diseases, but not in healthy subjects. This leaking leads to loss of tolerance toward this self-protein and the development of autoantibodies. In this study, clinical significance of both IFI16 protein and anti-IFI16 antibodies in rheumatoid arthritis (RA) was investigated. Methods. IFI16 protein and anti-IFI16 antibody levels were assessed by enzyme-linked immunosorbent assay in serum samples from 154 RA patients and 182 healthy controls, and in synovial fluid (SF) samples from 21 RA patients and 25 patients with osteoarthritis (OA). Results. Mean serum levels for both IFI16 and anti-IFI16 antibodies were higher in RA patients than in healthy controls, with a direct correlation between IFI16 concentration and anti-IFI16 antibody titer. The majority of RA patients with detectable circulating IFI16 protein were also positive for rheumatoid factor (RF)/anti-cyclic citrullinated peptide antibody (anti-CCP). The latter group was found to be positive for anti-IFI16 antibodies as well. The mean SF concentrations of both IFI16 protein and anti-IFI16 antibodies were higher in RA patients when compared with control OA patients. Interestingly, the presence of circulating IFI16 protein, but not anti-IFI16 antibodies, significantly correlated with RA-associated pulmonary disease. This correlation was not dependent on the presence of anti-IFI16 antibodies, sex, and smoking habit.Conclusion. Our data demonstrate that the high levels of circulating IFI16 in RA are more frequent in RF/anti-CCPpositive RA patients and significantly associated with pulmonary involvement. The relevance of circulating IFI16 protein as a new clinical biomarker of RA should be verified with additional studies.

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Section: Introductionsupporting

confidence: 52%

Section: Introductionmentioning

confidence: 52%

Section: Introductionmentioning

confidence: 99%

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Circulating Interferon‐Inducible Protein IFI16 Correlates With Clinical and Serological Features in Rheumatoid Arthritis

Alunno

Caneparo

Bistoni

et al. 2016

Arthritis Care & Research

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“…In addition to sensing and binding foreign DNA (15)(16)(17), IFI16 displays multifaceted activity due to its ability to bind to various target proteins (including transcription factors, signaling proteins, and tumor suppressor proteins) and to modulate a multitude of various cell and viral functions (12,13,(18)(19)(20)(21)(22)(23). IFI16 has been shown to interact with the tegument protein pp65 of HCMV at the major immediate-early promoter/enhancer (MIEP) early during infection, resulting in the upregulation of IE protein expression (20).…”

mentioning

confidence: 99%

Regulatory Interaction between the Cellular Restriction Factor IFI16 and Viral pp65 (pUL83) Modulates Viral Gene Expression and IFI16 Protein Stability

Biolatti

Dell’Oste

Pautasso

et al. 2016

J Virol

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A key player in the intrinsic resistance against human cytomegalovirus (HCMV) is the interferon-␥-inducible protein 16 (IFI16), which behaves as a viral DNA sensor in the first hours postinfection and as a repressor of viral gene transcription in the later stages. Previous studies on HCMV replication demonstrated that IFI16 binds to the viral protein kinase pUL97, undergoes phosphorylation, and relocalizes to the cytoplasm of infected cells. In this study, we demonstrate that the tegument protein pp65 (pUL83) recruits IFI16 to the promoter of the UL54 gene and downregulates viral replication, as shown by use of the HCMV mutant v65Stop, which lacks pp65 expression. Interestingly, at late time points of HCMV infection, IFI16 is stabilized by its interaction with pp65, which stood in contrast to IFI16 degradation, observed in herpes simplex virus 1 (HSV-1)-infected cells. Moreover, we found that its translocation to the cytoplasm, in addition to pUL97, strictly depends on pp65, as demonstrated with the HCMV mutant RV-VM1, which expresses a form of pp65 unable to translocate into the cytoplasm. Thus, these data reveal a dual role for pp65: during early infection, it modulates IFI16 activity at the promoter of immediate-early and early genes; subsequently, it delocalizes IFI16 from the nucleus into the cytoplasm, thereby stabilizing and protecting it from degradation. Overall, these data identify a novel activity of the pp65/IFI16 interactome involved in the regulation of UL54 gene expression and IFI16 stability during early and late phases of HCMV replication. IMPORTANCEThe DNA sensor IFI16, a member of the PYHIN proteins, restricts HCMV replication by impairing viral DNA synthesis. Using a mutant virus lacking the tegument protein pp65 (v65Stop), we demonstrate that pp65 recruits IFI16 to the early UL54 gene promoter. As a putative counteraction to its restriction activity, pp65 supports the nucleocytoplasmic export of IFI16, which was demonstrated with the viral mutant RV-VM1 expressing a nuclearly retained pp65. These data reveal a dual role of pp65 in IFI16 regulation: in the early phase of HCMV infection, it contributes to viral evasion from IFI16 restriction activity, while at later time points, it promotes the nuclear delocalization of IFI16, thereby stabilizing and protecting it from degradation. In the present work, we further clarify the mechanisms HCMV relies on to overcome intracellular innate immune restriction and provide new insights into the relevance of DNA-sensing restriction factor IFI16 during HCMV infection. Human cytomegalovirus (HCMV) is a member of the Betaherpesvirinae subfamily of Herpesviridae. It is a widespread pathogen that infects the majority of the world's population by early adulthood (1). The virus establishes a lifelong infection with some cells being latently infected, a state in which the virus resides in a nonproductive form, while other cells show a low-level persistent productive infection in which the virus is not cleared from the organism and is periodically reactiv...

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“…Further analysis is required to clarify whether IFI16‐β might cooperate with IFI16‐α to exert this function. Under some circumstances such as viral infection and inhibition of deacetylases, a portion of IFI16‐α could translocate into the cytoplasm, bind with dsDNA using its HIN domains, and induce STING‐dependent type I IFN expression . Cooperation between IFI16‐α and cGAS as well as potentiation of cGAMP production and function by IFI16‐α has also been described .…”

Section: Discussionmentioning

confidence: 99%

Inhibition of AIM 2 inflammasome activation by a novel transcript isoform of IFI 16

Wang

Deng

et al. 2018

EMBO Reports

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Mouse p202 is a disease locus for lupus and a dominant-negative inhibitor of AIM2 inflammasome activation. A human homolog of p202 has not been identified so far. Here, we report a novel transcript isoform of human IFI16-designated IFI16-β, which has a domain architecture similar to that of mouse p202. Like p202, IFI16-β contains two HIN domains, but lacks the pyrin domain. IFI16-β is ubiquitously expressed in various human tissues and cells. Its mRNA levels are also elevated in leukocytes of patients with lupus, virus-infected cells, and cells treated with interferon-β or phorbol ester. IFI16-β co-localizes with AIM2 in the cytoplasm, whereas IFI16-α is predominantly found in the nucleus. IFI16-β interacts with AIM2 to impede the formation of a functional AIM2-ASC complex. In addition, IFI16-β sequesters cytoplasmic dsDNA and renders it unavailable for AIM2 sensing. Enforced expression of IFI16-β inhibits the activation of AIM2 inflammasome, whereas knockdown of IFI16-β augments interleukin-1β secretion triggered by dsDNA but not dsRNA Thus, cytoplasm-localized IFI16-β is functionally equivalent to mouse p202 that exerts an inhibitory effect on AIM2 inflammasome.

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Mislocalization of the interferon inducible protein IFI16 by environmental insults: Implications in autoimmunity

Cited by 20 publications

References 61 publications

Circulating Interferon‐Inducible Protein IFI16 Correlates With Clinical and Serological Features in Rheumatoid Arthritis

Circulating Interferon‐Inducible Protein IFI16 Correlates With Clinical and Serological Features in Rheumatoid Arthritis

Regulatory Interaction between the Cellular Restriction Factor IFI16 and Viral pp65 (pUL83) Modulates Viral Gene Expression and IFI16 Protein Stability

Inhibition of AIM 2 inflammasome activation by a novel transcript isoform of IFI 16

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