Structural basis for IL-1α recognition by a modified DNA aptamer that specifically inhibits IL-1α signaling

Ren, Xiao‐Ming; Gelinas, Amy D.; Carlowitz, Ira von; Janjić, Nebojša; Pyle, Anna Marie

doi:10.1038/s41467-017-00864-2

Cited by 53 publications

(48 citation statements)

References 70 publications

(94 reference statements)

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“…Ren et al (36) recently conducted a crystallization experiment using IL-1a and IL-1b specific binding with a modified DNA aptamer (SL1067) with 2-naphthylmethyl substitutions at the 5-position of deoxyuridine (2Nap-dU) in order to solve the crystal structure of IL-1a. They observed that IL-1a binds to SL1067 with 7.3 mM affinity, whereas IL-1b shows no interaction, suggesting that IL-1a has intrinsic properties to bind DNA without a cointeracting protein to assist in transcription regulation.…”

Section: Discussionmentioning

confidence: 99%

Critical role of IL‐1α in IL‐1β‐induced inflammatory responses: cooperation with NF‐κBp65 in transcriptional regulation

Singh¹,

Fechtner²,

Chourasia

et al. 2018

FASEB j.

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The IL‐1 cytokines are considered among the first family of cytokines that orchestrate acute and chronic inflammatory diseases. Both IL‐1β and IL‐1α are members of the IL‐1 family; however, their distinct roles in the inflammatory processes remain poorly understood. We explored the role of IL‐1α in IL‐1β‐activated signaling pathways causing synovial inflammation in rheumatoid arthritis (RA). Using synovial fibroblasts isolated from RA joints, we found that IL‐1β significantly stimulated IL‐1α expression, which was selectively inhibited by blocking the NF‐κB pathway. Knockdown of IL‐1α using small interfering RNA abolished IL‐1β‐induced pro‐IL‐1α and pro‐IL‐1β expression and suppressed inflammation. Native and chromatin immunoprecipitation studies showed that IL‐1α cooperates in NF‐κBp65 binding to the distal region of IL‐1α promoter and to the proximal region of IL‐1β promoter upstream of the transcription start site to stabilize their gene transcription. Molecular dynamics simulation of IL‐1α or IL‐1β binding to IL‐1 receptor showed distinct interaction sites that corroborate with the ability of IL‐1α to differentially activate phosphorylation of signaling proteins compared with IL‐1β. Our study highlights the importance of IL‐1α in mediating IL‐1β–induced inflammation in addition to maintaining its expression and providing a rationale for targeting IL‐1α to minimize the role of IL‐1β in inflammatory diseases like RA.—Singh, A. K., Fechtner, S., Chourasia, M., Sicalo, J., Ahmed, S. Critical role of IL‐1α in IL‐1β–induced inflammatory responses: cooperation with NF‐κBp65 in transcriptional regulation. FASEB J. 33, 2526–2536 (2019). http://www.fasebj.org

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Section: Discussionmentioning

confidence: 99%

Critical role of IL‐1α in IL‐1β‐induced inflammatory responses: cooperation with NF‐κBp65 in transcriptional regulation

Singh¹,

Fechtner²,

Chourasia

et al. 2018

FASEB j.

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“…A total of six ssDNA aptamer probes with a length of 86 nt were identified using multiple sequence alignment analysis by DNAMAN software. Considering the important role that secondary structures play in the recognition capacity of aptamers 48 , 49 , the secondary structures of the six selected aptamer probes were also analyzed and found to be composed of various stem-loop and hairpin structures ( Figure S3 ). Probes sk1, sk2, sk3, sk4, sk5, and sk6 accounted for 50%, 3.3%, 13.3%, 16.7%, 13.3%, and 3.3% of all positive clones, respectively ( Table 1 ).…”

Section: Resultsmentioning

confidence: 99%

An Aptamer-Based Probe for Molecular Subtyping of Breast Cancer

Liu¹,

Wang²,

Tan³

et al. 2018

Theranostics

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Molecular subtyping of breast cancer is of considerable interest owing to its potential for personalized therapy and prognosis. However, current methodologies cannot be used for precise subtyping, thereby posing a challenge in clinical practice. The aim of the present study is to develop a cell-specific single-stranded DNA (ssDNA) aptamer-based fluorescence probe for molecular subtyping of breast cancer.Methods: Cell-SELEX method was utilized to select DNA aptamers. Flow cytometry and confocal microscopy were used to study the specificity, binding affinity, temperature effect on the binding ability and target type analysis of the aptamers. In vitro and in vivo fluorescence imaging were used to distinguish the molecular subtypes of breast cancer cells, tissue sections and tumor-bearing mice.Results: Six SK-BR-3 breast cancer cell-specific ssDNA aptamers were evolved after successive in vitro selection over 21 rounds by Cell-SELEX. The Kd values of the selected aptamers were all in the low-nanomolar range, among which aptamer sk6 showed the lowest Kd of 0.61 ± 0.14 nM. Then, a truncated aptamer-based probe, sk6Ea, with only 53 nt and high specificity and binding affinity to the target cells was obtained. This aptamer-based probe was able to 1) differentiate SK-BR-3, MDA-MB-231, and MCF-7 breast cancer cells, as well as distinguish breast cancer cells from MCF-10A normal human mammary epithelial cells; 2) distinguish HER2-enriched breast cancer tissues from Luminal A, Luminal B, triple-negative breast cancer tissues, and adjacent normal breast tissues (ANBTs) in vitro; and 3) distinguish xenografts of SK-BR-3 tumor-bearing mice from those of MDA-MB-231 and MCF-7 tumor-bearing mice within 30 min in vivo.Conclusion: The results suggest that the aptamer-based probe is a powerful tool for fast and highly sensitive subtyping of breast cancer both in vitro and in vivo and is also very promising for the identification, diagnosis, and targeted therapy of breast cancer molecular subtypes.

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“…Enhancement in the chemical diversity of these random nucleic acid libraries, even with one and the same modification at only one of the four bases (e.g., at a 5-position of a pyrimidine throughout the library), can dramatically improve both the success rate of DNA-based SELEX experiments and the binding affinities of the resulting aptamers (14)(15)(16). Crystal structures of these SOMAmer reagents (slow offrate modified aptamers) bound to their cognate proteins make it clear that the pyrimidine adducts of SOMAmers form direct contacts with the protein and participate in shaping the binding interface, much like amino acid residues in proteins (17)(18)(19)(20)(21). As importantly, these crystal structures also show that the hydrophobic "side chains" of the modified bases participate in internal motifs that stabilize the folded structures (19).…”

Section: Discussionmentioning

confidence: 99%

Modified nucleotides may have enhanced early RNA catalysis

Wolk

Mayfield

Gelinas

et al. 2020

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

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The modern version of the RNA World Hypothesis begins with activated ribonucleotides condensing (nonenzymatically) to make RNA molecules, some of which possess (perhaps slight) catalytic activity. We propose that noncanonical ribonucleotides, which would have been inevitable under prebiotic conditions, might decrease the RNA length required to have useful catalytic function by allowing short RNAs to possess a more versatile collection of folded motifs. We argue that modified versions of the standard bases, some with features that resemble cofactors, could have facilitated that first moment in which early RNA molecules with catalytic capability began their evolutionary path toward self-replication.

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Structural basis for IL-1α recognition by a modified DNA aptamer that specifically inhibits IL-1α signaling

Cited by 53 publications

References 70 publications

Critical role of IL‐1α in IL‐1β‐induced inflammatory responses: cooperation with NF‐κBp65 in transcriptional regulation

Critical role of IL‐1α in IL‐1β‐induced inflammatory responses: cooperation with NF‐κBp65 in transcriptional regulation

An Aptamer-Based Probe for Molecular Subtyping of Breast Cancer

Modified nucleotides may have enhanced early RNA catalysis

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