Mutually Exclusive Roles of SHARPIN in Integrin Inactivation and NF-κB Signaling.
SHANK-associated RH domain interactor (SHARPIN) inhibits integrins through interaction with the integrin α-subunit. In addition, SHARPIN enhances nuclear factor-kappaB (NF-κB) activity as a component of the linear ubiquitin chain assembly complex (LUBAC). However, it is currently unclear how regulat...
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doaj-53e347ddde994722a02692ca70f9dc622020-11-25T02:30:16ZengPublic Library of Science (PLoS)PLoS ONE1932-62032015-01-011011e014342310.1371/journal.pone.0143423Mutually Exclusive Roles of SHARPIN in Integrin Inactivation and NF-κB Signaling.Nicola De FranceschiEmilia PeuhuMaddy ParsonsSami RissanenIlpo VattulainenMarko SalmiJohanna IvaskaJeroen PouwelsSHANK-associated RH domain interactor (SHARPIN) inhibits integrins through interaction with the integrin α-subunit. In addition, SHARPIN enhances nuclear factor-kappaB (NF-κB) 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 α-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-κB activity, respectively. Altogether these data suggest that the roles of SHARPIN in inhibiting integrin activity and supporting linear ubiquitination are (molecularly) distinct.http://europepmc.org/articles/PMC4658161?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Nicola De Franceschi Emilia Peuhu Maddy Parsons Sami Rissanen Ilpo Vattulainen Marko Salmi Johanna Ivaska Jeroen Pouwels |
spellingShingle |
Nicola De Franceschi Emilia Peuhu Maddy Parsons Sami Rissanen Ilpo Vattulainen Marko Salmi Johanna Ivaska Jeroen Pouwels Mutually Exclusive Roles of SHARPIN in Integrin Inactivation and NF-κB Signaling. PLoS ONE |
author_facet |
Nicola De Franceschi Emilia Peuhu Maddy Parsons Sami Rissanen Ilpo Vattulainen Marko Salmi Johanna Ivaska Jeroen Pouwels |
author_sort |
Nicola De Franceschi |
title |
Mutually Exclusive Roles of SHARPIN in Integrin Inactivation and NF-κB Signaling. |
title_short |
Mutually Exclusive Roles of SHARPIN in Integrin Inactivation and NF-κB Signaling. |
title_full |
Mutually Exclusive Roles of SHARPIN in Integrin Inactivation and NF-κB Signaling. |
title_fullStr |
Mutually Exclusive Roles of SHARPIN in Integrin Inactivation and NF-κB Signaling. |
title_full_unstemmed |
Mutually Exclusive Roles of SHARPIN in Integrin Inactivation and NF-κB Signaling. |
title_sort |
mutually exclusive roles of sharpin in integrin inactivation and nf-κb signaling. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2015-01-01 |
description |
SHANK-associated RH domain interactor (SHARPIN) inhibits integrins through interaction with the integrin α-subunit. In addition, SHARPIN enhances nuclear factor-kappaB (NF-κB) 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 α-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-κB activity, respectively. Altogether these data suggest that the roles of SHARPIN in inhibiting integrin activity and supporting linear ubiquitination are (molecularly) distinct. |
url |
http://europepmc.org/articles/PMC4658161?pdf=render |
work_keys_str_mv |
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