Inhibition of IRF5 cellular activity with cell-penetrating peptides that target homodimerization
Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC)..
The transcription factor interferon regulatory factor 5 (IRF5) plays essential roles in pathogen-induced immunity downstream of Toll-, nucleotide-binding oligomerization domain-, and retinoic acid-inducible gene I-like receptors and is an autoimmune susceptibility gene. Normally, inactive in the cytoplasm, upon stimulation, IRF5 undergoes posttranslational modification(s), homodimerization, and nuclear translocation, where dimers mediate proinflammatory gene transcription. Here, we report the rational design of cell-penetrating peptides (CPPs) that disrupt IRF5 homodimerization. Biochemical and imaging analysis shows that IRF5-CPPs are cell permeable, noncytotoxic, and directly bind to endogenous IRF5. IRF5-CPPs were selective and afforded cell type- and species-specific inhibition. In plasmacytoid dendritic cells, inhibition of IRF5-mediated interferon-α production corresponded to a dose-dependent reduction in nuclear phosphorylated IRF5 [p(Ser462)IRF5], with no effect on pIRF5 levels. These data support that IRF5-CPPs function downstream of phosphorylation. Together, data support the utility of IRF5-CPPs as novel tools to probe IRF5 activation and function in disease.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:6 |
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| Enthalten in: |
Science advances - 6(2020), 20 vom: 14. Mai, Seite eaay1057 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Banga, Jaspreet [VerfasserIn] |
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| Links: |
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| Themen: |
Cell-Penetrating Peptides |
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| Anmerkungen: |
Date Completed 08.04.2022 Date Revised 16.05.2023 published: Electronic-eCollection Citation Status MEDLINE |
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| doi: |
10.1126/sciadv.aay1057 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM310227860 |
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| 245 | 1 | 0 | |a Inhibition of IRF5 cellular activity with cell-penetrating peptides that target homodimerization |
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| 520 | |a Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). | ||
| 520 | |a The transcription factor interferon regulatory factor 5 (IRF5) plays essential roles in pathogen-induced immunity downstream of Toll-, nucleotide-binding oligomerization domain-, and retinoic acid-inducible gene I-like receptors and is an autoimmune susceptibility gene. Normally, inactive in the cytoplasm, upon stimulation, IRF5 undergoes posttranslational modification(s), homodimerization, and nuclear translocation, where dimers mediate proinflammatory gene transcription. Here, we report the rational design of cell-penetrating peptides (CPPs) that disrupt IRF5 homodimerization. Biochemical and imaging analysis shows that IRF5-CPPs are cell permeable, noncytotoxic, and directly bind to endogenous IRF5. IRF5-CPPs were selective and afforded cell type- and species-specific inhibition. In plasmacytoid dendritic cells, inhibition of IRF5-mediated interferon-α production corresponded to a dose-dependent reduction in nuclear phosphorylated IRF5 [p(Ser462)IRF5], with no effect on pIRF5 levels. These data support that IRF5-CPPs function downstream of phosphorylation. Together, data support the utility of IRF5-CPPs as novel tools to probe IRF5 activation and function in disease | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Research Support, U.S. Gov't, Non-P.H.S. | |
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| 650 | 7 | |a Interferon Regulatory Factors |2 NLM | |
| 700 | 1 | |a Srinivasan, Dinesh |e verfasserin |4 aut | |
| 700 | 1 | |a Sun, Chia-Chi |e verfasserin |4 aut | |
| 700 | 1 | |a Thompson, Cherrie D |e verfasserin |4 aut | |
| 700 | 1 | |a Milletti, Francesca |e verfasserin |4 aut | |
| 700 | 1 | |a Huang, Kuo-Sen |e verfasserin |4 aut | |
| 700 | 1 | |a Hamilton, Shannon |e verfasserin |4 aut | |
| 700 | 1 | |a Song, Su |e verfasserin |4 aut | |
| 700 | 1 | |a Hoffman, Ann F |e verfasserin |4 aut | |
| 700 | 1 | |a Qin, Yajuan Gu |e verfasserin |4 aut | |
| 700 | 1 | |a Matta, Bharati |e verfasserin |4 aut | |
| 700 | 1 | |a LaPan, Margaret |e verfasserin |4 aut | |
| 700 | 1 | |a Guo, Qin |e verfasserin |4 aut | |
| 700 | 1 | |a Lu, Gang |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Dan |e verfasserin |4 aut | |
| 700 | 1 | |a Qian, Hong |e verfasserin |4 aut | |
| 700 | 1 | |a Bolin, David R |e verfasserin |4 aut | |
| 700 | 1 | |a Liang, Lena |e verfasserin |4 aut | |
| 700 | 1 | |a Wartchow, Charles |e verfasserin |4 aut | |
| 700 | 1 | |a Qiu, Jin |e verfasserin |4 aut | |
| 700 | 1 | |a Downing, Michelle |e verfasserin |4 aut | |
| 700 | 1 | |a Narula, Satwant |e verfasserin |4 aut | |
| 700 | 1 | |a Fotouhi, Nader |e verfasserin |4 aut | |
| 700 | 1 | |a DeMartino, Julie A |e verfasserin |4 aut | |
| 700 | 1 | |a Tan, Seng-Lai |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Gang |e verfasserin |4 aut | |
| 700 | 1 | |a Barnes, Betsy J |e verfasserin |4 aut | |
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