Inhibition of IRF5 cellular activity with cell-penetrating peptides that target homodimerization

被引：19

作者：

Banga, Jaspreet ^{[1
]}

Srinivasan, Dinesh ^{[2
,7
]}

Sun, Chia-Chi ^{[3
]}

Thompson, Cherrie D. ^{[1
]}

Milletti, Francesca ^{[4
,8
]}

Huang, Kuo-Sen ^{[2
]}

Hamilton, Shannon ^{[2
]}

Song, Su ^{[1
]}

Hoffman, Ann F. ^{[2
,9
]}

Qin, Yajuan Gu ^{[2
]}

Matta, Bharati ^{[1
]}

Lapan, Margaret ^{[1
]}

Guo, Qin ^{[1
]}

Lu, Gang ^{[2
]}

Li, Dan ^{[1
]}

Qian, Hong ^{[2
,10
]}

Bolin, David R. ^{[2
]}

Liang, Lena ^{[2
]}

Wartchow, Charles ^{[2
]}

Qiu, Jin ^{[3
]}

Downing, Michelle ^{[3
]}

Narula, Satwant ^{[2
]}

Fotouhi, Nader ^{[2
]}

Demartino, Julie A. ^{[2
,3
]}

Tan, Seng-Lai ^{[2
]}

Chen, Gang ^{[2
,3
]}

Barnes, Betsy J. ^{[1
,5
,6
]}

机构：

[1] Feinstein Inst Med Res, Ctr Autoimmune Musculoskeletal & Hematopoiet Dis, 350 Community Dr, Manhasset, NY 11030 USA

[2] Hoffmann La Roche Inc, 340 Kingsland St, Nutley, NJ 07110 USA

[3] EMD Serono Res & Dev Inst Inc, 45A Middlesex Turnpike, Billerica, MA 01821 USA

[4] Roche Innovat Ctr NewYork, 430 East 29th St, New York, NY 10016 USA

[5] Zucker Sch Med Hofstra Northwell, Dept Mol Med, Hempstead, NY 11549 USA

[6] Zucker Sch Med Hofstra Northwell, Dept Pediat, Hempstead, NY 11549 USA

[7] AzurRx BioPharma Inc, Downstate Biotechnol Incubator, 760 Parkside Ave,Suite 304, Brooklyn, NY 11226 USA

[8] Kite Pharma, 1800 Stewart St, Santa Monica, CA 90404 USA

[9] GlaxoSmithKline, Platform Technol & Sci, 1250 S Collegeville Rd, Collegeville, PA 19426 USA

[10] Novartis Pharmaceut, 1 Hlth Plaza, E Hanover, NJ 07936 USA

来源：

SCIENCE ADVANCES | 2020年 / 6卷 / 20期

关键词：

INTERFERON REGULATORY FACTOR; STRONG RISK-FACTOR; TRANSCRIPTION FACTOR; GENETIC-VARIANTS; MACROPHAGE POLARIZATION; IRF5(-/-) MICE; IKK-BETA; LUPUS; INTERFERON-REGULATORY-FACTOR-5; ACTIVATION;

D O I：

10.1126/sciadv.aay1057

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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-alpha production corresponded to a dose-dependent reduction in nuclear phosphorylated IRF5 [p(Ser(462))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.

引用

页数：16

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