Regulation of STING activation and its impact in inflammatory diseases

Responsable du Stage : Bénédicte Manoury

Tél : 0140615382 E-mail:  benedicte.manoury@inserm.fr,

Institut Necker Enfants Malades

Résumé du Projet de Stage 

UNC93B1, a highly conserved 12-membrane spanning molecule residing in the endoplasmic reticulum (ER), has been identified as a key regulator in the trafficking1 and folding2 to endosomes of intracellular Toll-like receptors (TLRs) that detect microbial nucleic acids. Indeed, a mutation in the Unc93b1 gene (3d mutation) results in inhibition of intracellular TLRs signalling in dendritic cells (DCs). We have shown that UNC93B1, but not the 3d mutant, also binds the Ca2+ sensor stromal interaction molecule 1 or STIM1 in the ER3 and that this association is essential for antigen cross presentation3, 4. Recently the group of Gwack5 has demonstrated abnormal localisation of STING (stimulator of interferon genes) in cells deficient for STIM1, resulting in enhanced type I interferon secretion at the steady state. Indeed, STIM1 is required for STING localisation in the ER and the absence of STIM1 triggers STING trafficking to the Golgi apparatus and its activation. STING is a protein critical for type I interferon response to pathogens containing DNA and its abnormal activation is associated to inflammation and autoimmunity. Our preliminary data and recent published report6 indicate a role for UNC3B1 in STING localisation and signalling. Thus, this project aims at studying the role of UNC93B1 in STING trafficking and activation and its link in autoimmunity and inflammatory diseases.

  1. Lee BL et al, 2013. Elife 19;2:e00291. 2. Pelka K et al, 2018. Immunity 48:911-22. 3. Maschalidi S et al, 2017. Nat Comm 21;8(1):1640. 4. Nunes-Hasler P et al, 2017. Nat Comm 24;8(1):1852. 5. Srikanth P et al, 2019. Nat Immunol 20:152-162. 6. Ze H et al, 2021. Eur J Immunol 5:1672-1685.

Références:

– Tohme M,……, Manoury B. TLR7 trafficking and signaling in B cells is regulated by the MHC-II associated invariant chain. J Cell Science 2020 Mar 10;133(5):jcs236711. doi: 10.1242/jcs.236711.

– Maatouk L,……, Manoury B, Vyas S. TLR9 activation via microglial glucocorticoid receptors contributes to degeneration of midbrain dopamine neurons. Nat Commun 2018 Jun 22 ;9 (1)2450 doi: 10.1038/s41467-018-04569-y.

– Nunes-Hasler P,…., Manoury B, Demaurex N. STIM1 promotes migration, phagosomal maturation and antigen cross- presentation in dendritic cells. 2017 Nat Commun Nov 24;8(1):1852. doi: 10.1038/s41467-017-01600-6.

– Maschalidi S,……, Darasse-Jèze G, Manoury B. UNC93B1 interacts with the calcium sensor STIM1 for efficient antigen cross-presentation in dendritic cells. 2017 Nat Commun. Nov 21;8(1):1640. doi: 10.1038/s41467-017-01601-5.

– Babdor J,…., Manoury B* Saveanu L*. IRAP+ endosomes restrict TLR9 activation and signaling.  2017 Nat Immunol May;18(5):509-518doi: 10.1038/ni.3711. *Co-last and corresponding authors


Ce projet s’inscrit-il dans la perspective d’une thèse :

                                                       oui  x

                                                       non o

 si oui type de financement prévu : Financement par l’ED ou ANR

 Ecole Doctorale de rattachement : BioSPC ED 562  

Intitulé de l’Unité : Institut Necker Enfants Malades, INSERM U1151-CNRS UMR 8253

Equipe d’Accueil : « Réponse immune et signaux de danger » et « Immunité et métabolisme du diabète »

Nom du Responsable de l’Unité : Fabiola Terzi

Nom du Responsable de l’Équipe : Bénédicte Manoury- Nicolas Venteclef

Adresse : Institut Necker Enfants Malades 160 rue de Vaugirard 75015 Paris