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

12 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

Keywords

  • SHARPIN

Fingerprint Dive into the research topics of 'Mutually exclusive roles of SHARPIN in integrin inactivation and NF-[kappa]B signaling'. Together they form a unique fingerprint.

  • Cite this

    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, 10(11), [0143423]. https://doi.org/10.1371/journal.pone.0143423