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Cullin-5 adaptor SPSB1 controls NF-κB activation downstream of 1 multiple signalling pathways

Maluquer de Motes, Carlos and Georgana, Illiana (2019) Cullin-5 adaptor SPSB1 controls NF-κB activation downstream of 1 multiple signalling pathways Frontiers in Immunology.

Georgana and Maluquer de Motes_Frontiers in Immunology.pdf - Accepted version Manuscript

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Cullin-RING E3 ubiquitin ligases (CRLs) have emerged as critical regulators of many cellular functions including innate immunity and inflammation. CRLs form multiprotein complexes in which specific adaptor proteins recruit the substrates to be ubiquitylated. Here, we systematically depleted all predicted SOCS-box proteins – the substrate adaptors for the CRL5 family - and assessed the impact on the activation of the NF-κB pathway. Depletion of SPSB1 resulted in a significant increase in NF-κB activation, indicating the importance of SPSB1 as an NF-κB negative regulator. In agreement, overexpression of SPSB1 suppressed NF-κB activity in a potent, dose-dependent manner in response to various agonists. Conversely, the activation of IRF-3, AP-1 and STATs was unaffected by SPSB1, showing its specificity for NF-κB. Mechanistically, SPSB1 suppressed NF-κB activation induced via multiple pathways including Toll-like receptors and RNA and DNA sensing adaptors, but was unable to prevent the phosphorylation and degradation of IκB nor the translocation of p65 into the nucleus. This indicated that SPSB1 exerts its inhibitory activity downstream, or at the level, of the NF-κB heterodimer and in agreement, SPSB1 was found to co-precipitate with p65. Additionally, A549 cells stably expressing SPSB1 presented lower cytokine levels including type I interferon in response to cytokine stimulation and virus infection. Taken together, our results reveal novel regulatory mechanisms in inflammation and innate immune signalling and identify the prominent role of SPSB1 in controlling NF-κB activation, thus providing new opportunities for the therapeutic targeting of NF-κB transcriptional activity.

Item Type: Article
Divisions : Faculty of Health and Medical Sciences > School of Biosciences and Medicine
Authors :
Maluquer de Motes,
Georgana, Illiana
Date : 20 December 2019
Depositing User : James Marshall
Date Deposited : 27 Jan 2020 09:43
Last Modified : 27 Jan 2020 09:43

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