The matrix protein of rabies virus binds to RelAp43 to modulate NF-κB-dependent gene expression related to innate immunity

Khalifa, Youcef Ben; Luco, Sophie; Besson, Benoit; Sonthonnax, Florian; Archambaud, Medhi; Grimes, Jonathan M.; Larrous, Florence; Bourhy, Hervé

doi:10.1038/srep39420

Cited by 45 publications

(72 citation statements)

References 38 publications

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“…III IV I III RVC20 scFv RVC20 scFv II′ I′ IV′ III′ IV″ IV I II′ I′ IV′ IV″ III″ III III′ III″ IV IV″ II″ III III″ I″ I I ′ IV IV″ II″ III III″ I″ I I Recombinant IgG production. UA sequences were determined with reference to the IMGT database 27 and produced by gene synthesis (Genscript 29 . At 6 days post-transfection, the cells were serially passaged every 3 days.…”

Section: Methodsmentioning

confidence: 99%

Structure of the prefusion-locking broadly neutralizing antibody RVC20 bound to the rabies virus glycoprotein

et al. 2020

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Rabies virus (RABV) causes fatal encephalitis in more than 59,000 people yearly. Upon the bite of an infected animal, the development of clinical disease can be prevented with postexposure prophylaxis (PEP), which includes the administration of Rabies immunoglobulin (RIG). However, the high cost and limited availability of serum-derived RIG severely hamper its wide use in resource-limited countries. A safe low-cost alternative is provided by using broadly neutralizing monoclonal antibodies (bnAbs). Here we report the X-ray structure of one of the most potent and most broadly reactive human bnAbs, RVC20, in complex with its target domain III of the RABV glycoprotein (G). The structure reveals that the RVC20 binding determinants reside in a highly conserved surface of G, rationalizing its broad reactivity. We further show that RVC20 blocks the acid-induced conformational change required for membrane fusion. Our results may guide the future development of direct antiviral small molecules for Rabies treatment.

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Section: Methodsmentioning

confidence: 99%

Structure of the prefusion-locking broadly neutralizing antibody RVC20 bound to the rabies virus glycoprotein

et al. 2020

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“…Another viral protein, the matrix protein (M), is a small pleiotropic protein forming oligomers and involved in various functions such as structural organization of the viral particle or potentially in the formation of viral inclusions [ 14 , 15 ]. First involved in the dysregulation of cell homeostasis and induction of cell death [ 16 – 18 ], the M protein has been also shown to be associated with the inhibition of the NF-κB pathway through an interaction with RelAp43 [ 2 , 19 ]. Interestingly, only the M protein of field rabies virus (RABV) isolates such as the Thailand strain (M Tha ) was shown to interact with RelAp43, compared to attenuated viral strains such as the vaccinal PV or SAD virus (M SAD ).…”

Section: Introductionmentioning

confidence: 99%

“…Interestingly, only the M protein of field rabies virus (RABV) isolates such as the Thailand strain (M Tha ) was shown to interact with RelAp43, compared to attenuated viral strains such as the vaccinal PV or SAD virus (M SAD ). Recently, 4 residues of the M protein (position 77, 100, 104, 110) were shown to be involved in the interaction of M Tha with the C-ter part of RelAp43 and linked to the control of the expression of RelAp43-dependant genes [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

Regulation of NF-κB by the p105-ABIN2-TPL2 complex and RelAp43 during rabies virus infection

et al. 2017

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At the crossroad between the NF-κB and the MAPK pathways, the ternary complex composed of p105, ABIN2 and TPL2 is essential for the host cell response to pathogens. The matrix protein (M) of field isolates of rabies virus was previously shown to disturb the signaling induced by RelAp43, a NF-κB protein close to RelA/p65. Here, we investigated how the M protein disturbs the NF-κB pathway in a RelAp43-dependant manner and the potential involvement of the ternary complex in this mechanism. Using a tandem affinity purification coupled with mass spectrometry approach, we show that RelAp43 interacts with the p105-ABIN2-TPL2 complex and we observe a strong perturbation of this complex in presence of M protein. M protein interaction with RelAp43 is associated with a wide disturbance of NF-κB signaling, involving a modulation of IκBα-, IκBβ-, and IκBε-RelAp43 interaction and a favored interaction of RelAp43 with the non-canonical pathway (RelB and p100/p52). Monitoring the interactions between host and viral proteins using protein-fragment complementation assay and bioluminescent resonance energy transfer, we further show that RelAp43 is associated to the p105-ABIN2-TPL2 complex as RelAp43-p105 interaction stabilizes the formation of a complex with ABIN2 and TPL2. Interestingly, the M protein interacts not only with RelAp43 but also with TPL2 and ABIN2. Upon interaction with this complex, M protein promotes the release of ABIN2, which ultimately favors the production of RelAp43-p50 NF-κB dimers. The use of recombinant rabies viruses further indicates that this mechanism leads to the control of IFNβ, TNF and CXCL2 expression during the infection and a high pathogenicity profile in rabies virus infected mice. All together, our results demonstrate the important role of RelAp43 and M protein in the regulation of NF-κB signaling.

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“…The structures of both VSV and LABV M proteins have been solved [146], fueling the mechanistic appreciation of M assembly and opening a door towards structure-guided drug design against specific M microdomains. Attractive antiviral targets include M domains involved in M homo-oligomerization, interaction with host proteins, or required for binding to the viral G protein [17,18,70,125,126,[146][147][148][149][150][151].…”

Section: Direct-acting Antiviralsmentioning

confidence: 99%

Status of antiviral therapeutics against rabies virus and related emerging lyssaviruses

Pont

Plemper

Schnell

2019

Current Opinion in Virology

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Rabies virus (RABV) constitutes a major social and economic burden associated with 60,000 deaths annually worldwide. Although pre-and post-exposure treatment options are available, they are efficacious only when initiated prior to the onset of clinical symptoms. Aggravating the problem, the current RABV vaccine does not cross-protect against the emerging zoonotic phylogroup II lyssaviruses. A requirement for an uninterrupted cold chain and high cost of the immunoglobulin component of rabies prophylaxis generate an unmet need for the development of RABV-specific antivirals. We discuss desirable anti-RABV drug profiles, past efforts to address the problem and inhibitor candidates identified, and examine how the rapidly expanding structural insight into RABV protein organization has illuminated novel druggable target candidates and paved the way to structure-aided drug optimization. Special emphasis is given to the viral RNAdependent RNA polymerase complex as a promising target for direct-acting broad-spectrum RABV inhibitors.

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The matrix protein of rabies virus binds to RelAp43 to modulate NF-κB-dependent gene expression related to innate immunity

Cited by 45 publications

References 38 publications

Structure of the prefusion-locking broadly neutralizing antibody RVC20 bound to the rabies virus glycoprotein

Structure of the prefusion-locking broadly neutralizing antibody RVC20 bound to the rabies virus glycoprotein

Regulation of NF-κB by the p105-ABIN2-TPL2 complex and RelAp43 during rabies virus infection

Status of antiviral therapeutics against rabies virus and related emerging lyssaviruses

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