Characterization of distinct molecular interactions responsible for IRF3 and IRF7 phosphorylation and subsequent dimerization

Louise Dalskov; Ryo Narita; Line L. Andersen; Nanna Jensen; Sonia Assil; Kennith H. Kristensen; Jacob G. Mikkelsen; Takashi Fujita; Trine H. Mogensen; Søren R. Paludan; Rune Hartmann

doi:10.1093/nar/gkaa873

Characterization of distinct molecular interactions responsible for IRF₃ and IRF₇ phosphorylation and subsequent dimerization

Louise Dalskov, Ryo Narita, Line L. Andersen, Nanna Jensen, Sonia Assil, Kennith H. Kristensen, Jacob G. Mikkelsen, Takashi Fujita, Trine H. Mogensen, Søren R. Paludan, Rune Hartmann^*

^*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

Abstract

IRF3 and IRF7 are critical transcription factors in the innate immune response. Their activation is controlled by phosphorylation events, leading to the formation of homodimers that are transcriptionally active. Phosphorylation occurs when IRF3 is recruited to adaptor proteins via a positively charged surface within the regulatory domain of IRF3. This positively charged surface also plays a crucial role in forming the active homodimer by interacting with the phosphorylated sites stabilizing the homodimer. Here, we describe a distinct molecular interaction that is responsible for adaptor docking and hence phosphorylation as well as a separate interaction responsible for the formation of active homodimer. We then demonstrate that IRF7 can be activated by both MAVS and STING in a manner highly similar to that of IRF3 but with one key difference. Regulation of IRF7 appears more tightly controlled; while a single phosphorylation event is sufficient to activate IRF3, at least two phosphorylation events are required for IRF7 activation.

Original language	English
Journal	Nucleic Acids Research
Volume	48
Issue	20
Pages (from-to)	11421-11433
Number of pages	13
ISSN	0305-1048
DOIs	https://doi.org/10.1093/nar/gkaa873
Publication status	Published - Nov 2020

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10.1093/nar/gkaa873

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Dalskov, L., Narita, R., Andersen, L. L., Jensen, N., Assil, S., Kristensen, K. H., Mikkelsen, J. G., Fujita, T., Mogensen, T. H., Paludan, S. R., & Hartmann, R. (2020). Characterization of distinct molecular interactions responsible for IRF₃ and IRF₇ phosphorylation and subsequent dimerization. Nucleic Acids Research, 48(20), 11421-11433. https://doi.org/10.1093/nar/gkaa873

@article{b44c23f9405a47ba880bfab4cb578dcf,

title = "Characterization of distinct molecular interactions responsible for IRF3 and IRF7 phosphorylation and subsequent dimerization",

abstract = "IRF3 and IRF7 are critical transcription factors in the innate immune response. Their activation is controlled by phosphorylation events, leading to the formation of homodimers that are transcriptionally active. Phosphorylation occurs when IRF3 is recruited to adaptor proteins via a positively charged surface within the regulatory domain of IRF3. This positively charged surface also plays a crucial role in forming the active homodimer by interacting with the phosphorylated sites stabilizing the homodimer. Here, we describe a distinct molecular interaction that is responsible for adaptor docking and hence phosphorylation as well as a separate interaction responsible for the formation of active homodimer. We then demonstrate that IRF7 can be activated by both MAVS and STING in a manner highly similar to that of IRF3 but with one key difference. Regulation of IRF7 appears more tightly controlled; while a single phosphorylation event is sufficient to activate IRF3, at least two phosphorylation events are required for IRF7 activation.",

author = "Louise Dalskov and Ryo Narita and Andersen, {Line L.} and Nanna Jensen and Sonia Assil and Kristensen, {Kennith H.} and Mikkelsen, {Jacob G.} and Takashi Fujita and Mogensen, {Trine H.} and Paludan, {S{\o}ren R.} and Rune Hartmann",

year = "2020",

month = nov,

doi = "10.1093/nar/gkaa873",

language = "English",

volume = "48",

pages = "11421--11433",

journal = "Nucleic Acids Research",

issn = "0305-1048",

publisher = "Oxford University Press",

number = "20",

}

Characterization of distinct molecular interactions responsible for IRF₃ and IRF₇ phosphorylation and subsequent dimerization. / Dalskov, Louise ; Narita, Ryo; Andersen, Line L. et al.
In: Nucleic Acids Research, Vol. 48, No. 20, 11.2020, p. 11421-11433.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - Characterization of distinct molecular interactions responsible for IRF3 and IRF7 phosphorylation and subsequent dimerization

AU - Dalskov, Louise

AU - Narita, Ryo

AU - Andersen, Line L.

AU - Jensen, Nanna

AU - Assil, Sonia

AU - Kristensen, Kennith H.

AU - Mikkelsen, Jacob G.

AU - Fujita, Takashi

AU - Mogensen, Trine H.

AU - Paludan, Søren R.

AU - Hartmann, Rune

PY - 2020/11

Y1 - 2020/11

N2 - IRF3 and IRF7 are critical transcription factors in the innate immune response. Their activation is controlled by phosphorylation events, leading to the formation of homodimers that are transcriptionally active. Phosphorylation occurs when IRF3 is recruited to adaptor proteins via a positively charged surface within the regulatory domain of IRF3. This positively charged surface also plays a crucial role in forming the active homodimer by interacting with the phosphorylated sites stabilizing the homodimer. Here, we describe a distinct molecular interaction that is responsible for adaptor docking and hence phosphorylation as well as a separate interaction responsible for the formation of active homodimer. We then demonstrate that IRF7 can be activated by both MAVS and STING in a manner highly similar to that of IRF3 but with one key difference. Regulation of IRF7 appears more tightly controlled; while a single phosphorylation event is sufficient to activate IRF3, at least two phosphorylation events are required for IRF7 activation.

AB - IRF3 and IRF7 are critical transcription factors in the innate immune response. Their activation is controlled by phosphorylation events, leading to the formation of homodimers that are transcriptionally active. Phosphorylation occurs when IRF3 is recruited to adaptor proteins via a positively charged surface within the regulatory domain of IRF3. This positively charged surface also plays a crucial role in forming the active homodimer by interacting with the phosphorylated sites stabilizing the homodimer. Here, we describe a distinct molecular interaction that is responsible for adaptor docking and hence phosphorylation as well as a separate interaction responsible for the formation of active homodimer. We then demonstrate that IRF7 can be activated by both MAVS and STING in a manner highly similar to that of IRF3 but with one key difference. Regulation of IRF7 appears more tightly controlled; while a single phosphorylation event is sufficient to activate IRF3, at least two phosphorylation events are required for IRF7 activation.

UR - http://www.scopus.com/inward/record.url?scp=85096348642&partnerID=8YFLogxK

U2 - 10.1093/nar/gkaa873

DO - 10.1093/nar/gkaa873

M3 - Journal article

C2 - 33205822

AN - SCOPUS:85096348642

SN - 0305-1048

VL - 48

SP - 11421

EP - 11433

JO - Nucleic Acids Research

JF - Nucleic Acids Research

IS - 20

ER -

Characterization of distinct molecular interactions responsible for IRF₃ and IRF₇ phosphorylation and subsequent dimerization

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