Mutually exclusive roles of SHARPIN in integrin inactivation and NF-[kappa]B signaling

Nicola De Franceschi, Emilia Peuhu, Maddy Parsons, Sami Rissanen, Ilpo Vattulainen, Marko Salmi, Johanna Ivaska (Corresponding Author), Jerouen Pouwels (Corresponding Author)

Research output: Contribution to journalArticleScientificpeer-review

11 Citations (Scopus)

Abstract

SHANK-associated RH domain interactor (SHARPIN) inhibits integrins through interaction with the integrin a-subunit. In addition, SHARPIN enhances nuclear factor-kappaB (NF-?B) activity as a component of the linear ubiquitin chain assembly complex (LUBAC). However, it is currently unclear how regulation of these seemingly different roles is coordinated. Here, we show that SHARPIN binds integrin and LUBAC in a mutually exclusive manner. We map the integrin binding site on SHARPIN to the ubiquitin-like (UBL) domain, the same domain implicated in SHARPIN interaction with LUBAC component RNF31 (ring finger protein 31), and identify two SHARPIN residues (V267, L276) required for both integrin and RNF31 regulation. Accordingly, the integrin a-tail is capable of competing with RNF31 for SHARPIN binding in vitro. Importantly, the full SHARPIN RNF31-binding site contains residues (F263A/I272A) that are dispensable for SHARPIN-integrin interaction. Importantly, disrupting SHARPIN interaction with integrin or RNF31 abolishes SHARPIN-mediated regulation of integrin or NF-?B activity, respectively. Altogether these data suggest that the roles of SHARPIN in inhibiting integrin activity and supporting linear ubiquitination are (molecularly) distinct.
Original languageEnglish
Article number0143423
Number of pages16
JournalPLoS ONE
Volume10
Issue number11
DOIs
Publication statusPublished - 2015
MoE publication typeA1 Journal article-refereed

Fingerprint

NF-kappa B
integrins
Integrins
inactivation
Fingers
ubiquitin
Ubiquitin
proteins
binding sites
Proteins
Binding Sites
transcription factor NF-kappa B
Ubiquitination
Protein Binding
tail

Keywords

  • SHARPIN

Cite this

De Franceschi, N., Peuhu, E., Parsons, M., Rissanen, S., Vattulainen, I., Salmi, M., ... Pouwels, J. (2015). Mutually exclusive roles of SHARPIN in integrin inactivation and NF-[kappa]B signaling. PLoS ONE, 10(11), [0143423]. https://doi.org/10.1371/journal.pone.0143423
De Franceschi, Nicola ; Peuhu, Emilia ; Parsons, Maddy ; Rissanen, Sami ; Vattulainen, Ilpo ; Salmi, Marko ; Ivaska, Johanna ; Pouwels, Jerouen. / Mutually exclusive roles of SHARPIN in integrin inactivation and NF-[kappa]B signaling. In: PLoS ONE. 2015 ; Vol. 10, No. 11.
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abstract = "SHANK-associated RH domain interactor (SHARPIN) inhibits integrins through interaction with the integrin a-subunit. In addition, SHARPIN enhances nuclear factor-kappaB (NF-?B) activity as a component of the linear ubiquitin chain assembly complex (LUBAC). However, it is currently unclear how regulation of these seemingly different roles is coordinated. Here, we show that SHARPIN binds integrin and LUBAC in a mutually exclusive manner. We map the integrin binding site on SHARPIN to the ubiquitin-like (UBL) domain, the same domain implicated in SHARPIN interaction with LUBAC component RNF31 (ring finger protein 31), and identify two SHARPIN residues (V267, L276) required for both integrin and RNF31 regulation. Accordingly, the integrin a-tail is capable of competing with RNF31 for SHARPIN binding in vitro. Importantly, the full SHARPIN RNF31-binding site contains residues (F263A/I272A) that are dispensable for SHARPIN-integrin interaction. Importantly, disrupting SHARPIN interaction with integrin or RNF31 abolishes SHARPIN-mediated regulation of integrin or NF-?B activity, respectively. Altogether these data suggest that the roles of SHARPIN in inhibiting integrin activity and supporting linear ubiquitination are (molecularly) distinct.",
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De Franceschi, N, Peuhu, E, Parsons, M, Rissanen, S, Vattulainen, I, Salmi, M, Ivaska, J & Pouwels, J 2015, 'Mutually exclusive roles of SHARPIN in integrin inactivation and NF-[kappa]B signaling', PLoS ONE, vol. 10, no. 11, 0143423. https://doi.org/10.1371/journal.pone.0143423

Mutually exclusive roles of SHARPIN in integrin inactivation and NF-[kappa]B signaling. / De Franceschi, Nicola; Peuhu, Emilia; Parsons, Maddy; Rissanen, Sami; Vattulainen, Ilpo; Salmi, Marko; Ivaska, Johanna (Corresponding Author); Pouwels, Jerouen (Corresponding Author).

In: PLoS ONE, Vol. 10, No. 11, 0143423, 2015.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - Mutually exclusive roles of SHARPIN in integrin inactivation and NF-[kappa]B signaling

AU - De Franceschi, Nicola

AU - Peuhu, Emilia

AU - Parsons, Maddy

AU - Rissanen, Sami

AU - Vattulainen, Ilpo

AU - Salmi, Marko

AU - Ivaska, Johanna

AU - Pouwels, Jerouen

PY - 2015

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AB - SHANK-associated RH domain interactor (SHARPIN) inhibits integrins through interaction with the integrin a-subunit. In addition, SHARPIN enhances nuclear factor-kappaB (NF-?B) activity as a component of the linear ubiquitin chain assembly complex (LUBAC). However, it is currently unclear how regulation of these seemingly different roles is coordinated. Here, we show that SHARPIN binds integrin and LUBAC in a mutually exclusive manner. We map the integrin binding site on SHARPIN to the ubiquitin-like (UBL) domain, the same domain implicated in SHARPIN interaction with LUBAC component RNF31 (ring finger protein 31), and identify two SHARPIN residues (V267, L276) required for both integrin and RNF31 regulation. Accordingly, the integrin a-tail is capable of competing with RNF31 for SHARPIN binding in vitro. Importantly, the full SHARPIN RNF31-binding site contains residues (F263A/I272A) that are dispensable for SHARPIN-integrin interaction. Importantly, disrupting SHARPIN interaction with integrin or RNF31 abolishes SHARPIN-mediated regulation of integrin or NF-?B activity, respectively. Altogether these data suggest that the roles of SHARPIN in inhibiting integrin activity and supporting linear ubiquitination are (molecularly) distinct.

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M3 - Article

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JO - PLoS ONE

JF - PLoS ONE

SN - 1932-6203

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De Franceschi N, Peuhu E, Parsons M, Rissanen S, Vattulainen I, Salmi M et al. Mutually exclusive roles of SHARPIN in integrin inactivation and NF-[kappa]B signaling. PLoS ONE. 2015;10(11). 0143423. https://doi.org/10.1371/journal.pone.0143423