The proprotein convertase PC1/3 regulates TLR9 trafficking and the associated signaling pathways - Archive ouverte HAL Access content directly
Journal Articles Scientific Reports Year : 2016

The proprotein convertase PC1/3 regulates TLR9 trafficking and the associated signaling pathways

(1) , (1) , (1) , (2) , (2) , (1) , (1) , (2) , (1)
1
2

Abstract

Endosomal TLR9 is considered as a potent anti-tumoral therapeutic target. Therefore, it is crucial to decipher the mechanisms controlling its trafficking since it determines TLR9 activation and signalling. At present, the scarcity of molecular information regarding the control of this trafficking and signalling is noticeable. We have recently demonstrated that in macrophages, proprotein convertase 1/3 (PC1/3) is a key regulator of TLR4 Myd88-dependent signalling. In the present study, we established that PC1/3 also regulates the endosomal TLR9. Under CpG-ODN challenge, we found that PC1/3 traffics rapidly to co-localize with TLR9 in CpG-ODN-containing endosomes with acidic pH. In PC1/3 knockdown macrophages, compartmentalization of TLR9 was altered and TLR9 clustered in multivesicular bodies (MVB) as demonstrated by co-localization with Rab7. This demonstrates that PC1/3 controls TLR9 trafficking. This clustering of TLR9 in MVB dampened the anti-inflammatory STAT3 signalling pathway while it promoted the pro-inflammatory NF-kB pathway. As a result, macrophages from PC1/3 KO mice and rat PC1/3-KD NR8383 macrophages secreted more pro-inflammatory cytokines such as TNF-α, IL6, IL1α and CXCL2. This is indicative of a M1 pro-inflammatory phenotype. Therefore, PC1/3 KD macrophages represent a relevant mean for cell therapy as "Trojan" macrophages.
Fichier principal
Vignette du fichier
srep19360.pdf (4.89 Mo) Télécharger le fichier
Origin : Publication funded by an institution
Loading...

Dates and versions

inserm-02940434 , version 1 (16-09-2020)

Identifiers

Cite

M. Duhamel, F. Rodet, A. Murgoci, R. Desjardins, H. Gagnon, et al.. The proprotein convertase PC1/3 regulates TLR9 trafficking and the associated signaling pathways. Scientific Reports, 2016, 6, pp.19360. ⟨10.1038/srep19360⟩. ⟨inserm-02940434⟩

Collections

INSERM UNIV-LILLE
15 View
28 Download

Altmetric

Share

Gmail Facebook Twitter LinkedIn More