RPA nucleic acid-binding properties of IFI16-HIN200

Yan, Helen F.; Dalal, Kush; Hon, Benjamin; Youkharibache, Philippe; Lau, Desmond; Pio, Frederic

doi:10.1016/j.bbapap.2008.04.004

Cited by 45 publications

(41 citation statements)

References 43 publications

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“…1A]. This result indicated that full-length IFI16, unlike its isolated HIN200 domains (3,9,15), binds dsDNA in a cooperative manner. We then tested the binding of shorter dsDNA variants of VACV and HSV fragments that were used in the previous in vivo study (3).…”

Section: Resultsmentioning

confidence: 57%

“…2A). All lengths of ssDNA failed to show significant inhibition (15-72 bases), indicating that full-length IFI16 preferentially binds dsDNA despite the reported ssDNA-binding activity of IFI16 HinA (15) [ssAG60 shown as an example (30 repeats of adenosine and guanosine); Fig. 2A].…”

Section: Resultsmentioning

confidence: 99%

“…We reasoned that it is unlikely that regulation of IFI16 pathways is only accomplished by yet unknown downstream events. The currently prevailing mechanistic model for IFI16 was established by studying its isolated HIN200 domains, which nonspecifically bind any DNA exceeding their footprints equally well (3,9,15). In contrast, we hypothesized that studying the full-length protein might better address the DNA-sensing strategy of IFI16.…”

Section: Resultsmentioning

confidence: 99%

“…IFI16 is composed of two signature ALR domains, namely one N-terminal pyrin domain (PYD) (IFI16 PYD ) followed by two HIN200 domains (IFI16 HinA and IFI16 HinB ). The HIN200 domains nonspecifically bind various ss-and dsDNA fragments on the phosphate backbone via electrostatic interactions with a footprint of eight to nine bases, thus confirming that DNA sequence (e.g., the CpG island) is not a recognition element (9,(15)(16)(17). On the other hand, the PYD is a homotypic protein-protein interaction domain whose function is thought to be limited to recruiting downstream effectors (3, 9, 10).…”

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confidence: 95%

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Cooperative assembly of IFI16 filaments on dsDNA provides insights into host defense strategy

Morrone

Wang²,

Constantoulakis³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

153

209

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Whether host DNA receptors have any capacity to distinguish self from nonself at the molecular level is an outstanding question in the innate immunity of mammals. Here, by using quantitative assays and electron microscopy, we show that cooperatively assembling into filaments on dsDNA may serve as an integral mechanism by which human IFN-inducible protein-16 (IFI16) engages foreign DNA. IFI16 is essential for defense against a number of different pathogens, and its aberrant activity is also implicated in several autoimmune disorders, such as Sjögren syndrome. IFI16 cooperatively binds dsDNA in a length-dependent manner and clusters into distinct protein filaments even in the presence of excess dsDNA. Consequently, the assembled IFI16·dsDNA oligomers are clearly different from the conventional noninteracting entities resembling beads on a string. The isolated DNA-binding domains of IFI16 engage dsDNA without forming filaments and with weak affinity, and it is the non-DNA-binding pyrin domain of IFI16 that drives the cooperative filament assembly. The surface residues on the pyrin domain that mediate the cooperative DNA binding are conserved, suggesting that related receptors use a common mechanism. These results suggest that IFI16 clusters into signaling foci in a switch-like manner and that it is capable of using the size of naked dsDNA as a molecular ruler to distinguish self from nonself.cooperative filament formation | inflammasome R ecognition of foreign intracellular DNA is a widely conserved defense mechanism by which the innate immune system of mammals detects and responds to invading pathogens (1, 2). Using such a universal molecule as a major danger signal for detecting pathogens must be regulated in a stringent yet efficient manner. However, only a few deciding factors are known for the host innate immune system to selectively engage foreign DNA (i.e., nonself-DNA) while minimizing interactions with self-DNA, which include the compartmentalization of mammalian cells and the size of foreign DNA. These features, however, only raise more questions than provide answers. For example, the footprints of intracellular DNA receptors usually fall below 20 bp, and yet a long foreign DNA fragment [e.g., poly(dA:dT); ≥1,000 bp] is required to induce a robust innate immune response even in a normally DNA-free environment like the cytoplasm (1, 2). On the other hand, foreign DNA-sensing pathways also exist in the host nucleus in which DNA receptors must not respond to abundant self-DNA to prevent spurious activities (1, 2). Indeed, one of the major unresolved questions in understanding the DNA-sensing pathways of mammals is whether the host intracellular DNA receptors have any capacity to distinguish self-from nonself-DNA at the molecular level (2).Human IFN inducible protein-16 (IFI16) is an intracellular DNA receptor of innate immunity that belongs to the family of absent-in-melanoma-2 (AIM2)-like receptors (ALRs) (1-4). IFI16 senses DNA from invading pathogens in both the nucleus and cytoplasm [e.g., vaccinia virus...

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Section: Resultsmentioning

confidence: 57%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 95%

See 2 more Smart Citations

Cooperative assembly of IFI16 filaments on dsDNA provides insights into host defense strategy

Morrone

Wang²,

Constantoulakis³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

153

209

View full text Add to dashboard Cite

show abstract

“…2A). Both the HIN domains are known to bind DNA (55). However, they differ in their DNA-binding abilities.…”

Section: Hin Domains Of Ifi16mentioning

confidence: 99%

Role of the HIN Domain in Regulation of Innate Immune Responses

Shaw

Liu

2014

Molecular and Cellular Biology

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When DNA damage responses meet tumor immunity: From mechanism to therapeutic opportunity

Pan,

Wang,

Shen

et al. 2024

Intl Journal of Cancer

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DNA damage is a prevalent phenomenon in the context of cancer progression. Evidence suggests that DNA damage responses (DDR) are pivotal in overcoming tumor immune evasion. Alternatively, traditional radiotherapy and chemotherapy operate by inducing DNA damage, consequently stimulating the immune system to target tumors. The intricate interplay between signaling pathways involved in DDR and immune activation underscores the significance of considering both factors in developing improved immunotherapies. By delving deeper into the mechanisms underlying immune activation brought on by DNA damage, it becomes possible to identify novel treatment approaches that boost the anticancer immune response while minimizing undesirable side effects. This review explores the mechanisms behind DNA damage‐induced antitumor immune responses, the importance of DNA damage in antitumor immunity, and potential therapeutic approaches for cancer immunotherapy targeting DDR. Additionally, we discuss the challenges of combination therapy and strategies for integrating DNA damage‐targeting therapies with current cancer immunotherapy. In summary, this review highlights the critical role of DNA damage in tumor immunology, underscoring the potential of DDR inhibitors as promising therapeutic modalities for cancer treatment.

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RPA nucleic acid-binding properties of IFI16-HIN200

Cited by 45 publications

References 43 publications

Cooperative assembly of IFI16 filaments on dsDNA provides insights into host defense strategy

Cooperative assembly of IFI16 filaments on dsDNA provides insights into host defense strategy

Role of the HIN Domain in Regulation of Innate Immune Responses

When DNA damage responses meet tumor immunity: From mechanism to therapeutic opportunity

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