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Article ; Online: MARCH8 Ubiquitinates the Hepatitis C Virus Nonstructural 2 Protein and Mediates Viral Envelopment.

Kumar, Sathish / Barouch-Bentov, Rina / Xiao, Fei / Schor, Stanford / Pu, Szuyuan / Biquand, Elise / Lu, Albert / Lindenbach, Brett D / Jacob, Yves / Demeret, Caroline / Einav, Shirit

Cell reports

2019 Volume 26, Issue 7, Page(s) 1800–1814.e5

Abstract: The mechanisms that regulate envelopment of HCV and other viruses that bud intracellularly and/or lack late-domain motifs are largely unknown. We reported that K63 polyubiquitination of the HCV nonstructural (NS) 2 protein mediates HRS (ESCRT-0 component) ...

Abstract	The mechanisms that regulate envelopment of HCV and other viruses that bud intracellularly and/or lack late-domain motifs are largely unknown. We reported that K63 polyubiquitination of the HCV nonstructural (NS) 2 protein mediates HRS (ESCRT-0 component) binding and envelopment. Nevertheless, the ubiquitin signaling that governs NS2 ubiquitination remained unknown. Here, we map the NS2 interactome with the ubiquitin proteasome system (UPS) via mammalian cell-based screens. NS2 interacts with E3 ligases, deubiquitinases, and ligase regulators, some of which are candidate proviral or antiviral factors. MARCH8, a RING-finger E3 ligase, catalyzes K63-linked NS2 polyubiquitination in vitro and in HCV-infected cells. MARCH8 is required for infection with HCV, dengue, and Zika viruses and specifically mediates HCV envelopment. Our data reveal regulation of HCV envelopment via ubiquitin signaling and both a viral protein substrate and a ubiquitin K63-linkage of the understudied MARCH8, with potential implications for cell biology, virology, and host-targeted antiviral design.
MeSH term(s)	Cell Line, Tumor ; Endoplasmic Reticulum/metabolism ; HEK293 Cells ; Hepacivirus/metabolism ; Hepacivirus/pathogenicity ; Hepatitis C/genetics ; Hepatitis C/metabolism ; Hepatitis C/virology ; Humans ; Signal Transduction ; Ubiquitin/metabolism ; Ubiquitin-Protein Ligases/genetics ; Ubiquitin-Protein Ligases/metabolism ; Ubiquitination ; Viral Nonstructural Proteins/metabolism
Chemical Substances	NS2 protein, Hepatitis C virus ; Ubiquitin ; Viral Nonstructural Proteins ; MARCHF8 protein, human (EC 2.3.2.27) ; Ubiquitin-Protein Ligases (EC 2.3.2.27)
Language	English
Publishing date	2019-02-13
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2019.01.075
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Article ; Online: MARCH8 Ubiquitinates the Hepatitis C Virus Nonstructural 2 Protein and Mediates Viral Envelopment

Sathish Kumar / Rina Barouch-Bentov / Fei Xiao / Stanford Schor / Szuyuan Pu / Elise Biquand / Albert Lu / Brett D. Lindenbach / Yves Jacob / Caroline Demeret / Shirit Einav

Cell Reports, Vol 26, Iss 7, Pp 1800-1814.e

2019 Volume 5

Abstract: ... ubiquitination, hepatitis C virus, HCV, MARCH8, virus-host interactions, proteomics, assembly, envelopment ...

Abstract	Summary: The mechanisms that regulate envelopment of HCV and other viruses that bud intracellularly and/or lack late-domain motifs are largely unknown. We reported that K63 polyubiquitination of the HCV nonstructural (NS) 2 protein mediates HRS (ESCRT-0 component) binding and envelopment. Nevertheless, the ubiquitin signaling that governs NS2 ubiquitination remained unknown. Here, we map the NS2 interactome with the ubiquitin proteasome system (UPS) via mammalian cell-based screens. NS2 interacts with E3 ligases, deubiquitinases, and ligase regulators, some of which are candidate proviral or antiviral factors. MARCH8, a RING-finger E3 ligase, catalyzes K63-linked NS2 polyubiquitination in vitro and in HCV-infected cells. MARCH8 is required for infection with HCV, dengue, and Zika viruses and specifically mediates HCV envelopment. Our data reveal regulation of HCV envelopment via ubiquitin signaling and both a viral protein substrate and a ubiquitin K63-linkage of the understudied MARCH8, with potential implications for cell biology, virology, and host-targeted antiviral design. : The mechanisms that regulate intracellular viral envelopment are unknown. Kumar et al. report that MARCH8 catalyzes K63-linked polyubiquitination of the HCV nonstructural 2 protein and subsequently ESCRT recruitment and HCV envelopment. MARCH8 is required for infection with other Flaviviridae family members, thereby representing a potential host target for antiviral strategies. Keywords: ubiquitination, hepatitis C virus, HCV, MARCH8, virus-host interactions, proteomics, assembly, envelopment, intracellular membrane trafficking, ESCRT
Keywords	Biology (General) ; QH301-705.5
Subject code	570
Language	English
Publishing date	2019-02-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
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Article ; Online: Role of two modules controlling the interaction between SKAP1 and SRC kinases comparison with SKAP2 architecture and consequences for evolution.

Levillayer, Laurine / Brighelli, Camille / Demeret, Caroline / Sakuntabhai, Anavaj / Bureau, Jean-François

PloS one

2024 Volume 19, Issue 3, Page(s) e0296230

Abstract: SRC kinase associated phosphoprotein 1 (SKAP1), an adaptor for protein assembly, plays an important role in the immune system such as stabilizing immune synapses. Understanding how these functions are controlled at the level of the protein-protein ... ...

Abstract	SRC kinase associated phosphoprotein 1 (SKAP1), an adaptor for protein assembly, plays an important role in the immune system such as stabilizing immune synapses. Understanding how these functions are controlled at the level of the protein-protein interactions is necessary to describe these processes and to develop therapeutics. Here, we dissected the SKAP1 modular organization to recognize SRC kinases and compared it to that of its paralog SRC kinase associated phosphoprotein 2 (SKAP2). Different conserved motifs common to either both proteins or specific to SKAP2 were found using this comparison. Two modules harboring different binding properties between SKAP1 and SKAP2 were identified: one composed of two conserved motifs located in the second interdomain interacting at least with the SH2 domain of SRC kinases and a second one composed of the DIM domain modulated by the SH3 domain and the activation of SRC kinases. This work suggests a convergent evolution of the binding properties of some SRC kinases interacting specifically with either SKAP1 or SKAP2.
MeSH term(s)	src-Family Kinases/metabolism ; Phosphoproteins/metabolism ; Intracellular Signaling Peptides and Proteins/metabolism ; src Homology Domains
Chemical Substances	src kinase associated phosphoprotein 2 ; src-Family Kinases (EC 2.7.10.2) ; Phosphoproteins ; Intracellular Signaling Peptides and Proteins
Language	English
Publishing date	2024-03-14
Publishing country	United States
Document type	Journal Article
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0296230
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Article ; Online: Metabolomic changes in adults with status epilepticus: A human case-control study.

Hanin, Aurélie / Chollet, Céline / Demeret, Sophie / Di Meglio, Lucas / Castelli, Florence / Navarro, Vincent

Epilepsia

2024 Volume 65, Issue 4, Page(s) 929–943

Abstract: Objective: Status epilepticus (SE) is a life-threatening prolonged epileptic seizure that affects ~40 per 100 000 people yearly worldwide. The persistence of seizures may lead to excitotoxic processes, neuronal loss, and neuroinflammation, resulting in ... ...

Abstract	Objective: Status epilepticus (SE) is a life-threatening prolonged epileptic seizure that affects ~40 per 100 000 people yearly worldwide. The persistence of seizures may lead to excitotoxic processes, neuronal loss, and neuroinflammation, resulting in long-term neurocognitive and functional disabilities. A better understanding of the pathophysiological mechanisms underlying SE consequences is crucial for improving SE management and preventing secondary neuronal injury. Methods: We conducted a comprehensive untargeted metabolomic analysis, using liquid chromatography coupled with high-resolution mass spectrometry (LC-HRMS), on plasma and cerebrospinal fluid (CSF) samples from 78 adult patients with SE and 107 control patients without SE, including 29 with CSF for both groups. The metabolomic fingerprints were compared between patients with SE and controls. Metabolites with differences in relative abundances that could not be attributed to treatment or nutrition provided in the intensive care unit were isolated. Enrichment analysis was performed on these metabolites to identify the most affected pathways. Results: We identified 76 metabolites in the plasma and 37 in the CSF that exhibited differential expression in patients with SE compared to controls. The enrichment analysis revealed that metabolic dysregulations in patients with SE affected primarily amino acid metabolism (including glutamate, alanine, tryptophan, glycine, and serine metabolism), pyrimidine metabolism, and lipid homeostasis. Specifically, patients with SE had elevated levels of pyruvate, quinolinic acid, and keto butyric acid levels, along with lower levels of arginine, N-acetylaspartylglutamate (NAAG), tryptophan, uracil, and uridine. The tryptophan kynurenine pathway was identified as the most significantly altered in SE, resulting in the overproduction of quinolinic acid, an N-methyl-d-aspartate (NMDA) receptor agonist with pro-inflammatory properties. Significance: This study has identified several pathways that may play pivotal roles in SE consequences, such as the tryptophan kynurenine pathway. These findings offer novel perspectives for the development of neuroprotective therapeutics.
MeSH term(s)	Adult ; Humans ; Kynurenine/cerebrospinal fluid ; Tryptophan/metabolism ; Case-Control Studies ; Quinolinic Acid/cerebrospinal fluid ; Status Epilepticus ; Seizures
Chemical Substances	Kynurenine (343-65-7) ; Tryptophan (8DUH1N11BX) ; Quinolinic Acid (F6F0HK1URN)
Language	English
Publishing date	2024-02-10
Publishing country	United States
Document type	Journal Article
ZDB-ID	216382-2
ISSN	1528-1167 ; 0013-9580
ISSN (online)	1528-1167
ISSN	0013-9580
DOI	10.1111/epi.17899
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Article: Structure resolution of the trimeric RNA-dependent RNA polymerase of influenza viruses: impact on our understanding of polymerase interactions with host and viral factors.

Biquand, Élise / Demeret, Caroline

Virologie (Montrouge, France)

2020 Volume 20, Issue 6, Page(s) 302–320

Abstract: ... complex. The atomic-resolution of polymerase complexes from influenza virus type A, type B and type C came ...

Title translation	Résolution de la structure de l’ARN polymérase dépendante de l’ARN trimérique des virus influenza : son impact sur notre compréhension des interactions de la polymérase avec les facteurs viraux et cellulaires.
Abstract	Influenza viruses are segmented negative-sense RNA viruses whose RNA dependant RNA polymerase (RdRp) multiple activities multiple activities are central for the viral life cycle. The RdRp is composed of three subunits, PB1, PB2 and PA. It binds to the extremities of each vRNA segments encapsidated with multiple copies of the Nucleoprotein (NP), altogether constituting the viral ribonucleoprotein (vRNP). The RdRp performs both vRNA transcription and replication in the context of vRNP in the nuclei of infected cells. The temporal regulation of RdRp-associated activities is essential for the successful completion of the virus life cycle, but its understanding has been limited by the lack of structural information about the polymerase complex. The atomic-resolution of polymerase complexes from influenza virus type A, type B and type C came out in the past two years.We compile here the data provided by the near-concomitant resolution of several influenza polymerase crystal structures. We will highlight how structural information can contribute to our understanding of the interactions between the RdRp and viral or host factors.
Language	English
Publishing date	2020-02-25
Publishing country	France
Document type	Journal Article
ISSN	1267-8694
ISSN	1267-8694
DOI	10.1684/vir.2016.0672
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Article: Structure resolution of the trimeric RNA-dependent RNA polymerase of influenza viruses: impact on our understanding of polymerase interactions with host and viral factors.

Biquand, Elise / Demeret, Caroline

Virologie (Montrouge, France)

2020 Volume 20, Issue 6, Page(s) 32–48

Abstract: ... resolution of polymerase complexes from influenza virus type A, type B and type C came out in the past two ...

Abstract	Influenza viruses are segmented negative-sense RNA viruses whose RNA dependant RNA polymerase (RdRp) multiple activities are central for the viral life cycle. The RdRp is composed of three subunits, PB1, PB2 and PA. It binds to the extremities of each vRNA segments encapsidated with multiple copies of the Nucleoprotein (NP), altogether constituting the viral ribonucleoproteins (vRNPs). The RdRp performs both vRNA transcription and replication in the context of vRNP in the nuclei of infected cells. The temporal regulation of RdRp-associated activities is essential for the successful completion of the virus life cycle, but its understanding has been limited by the lack of structural information about the polymerase complex. The atomic-resolution of polymerase complexes from influenza virus type A, type B and type C came out in the past two years. We compile here the data provided by the near-concomitant resolution of several influenza polymerase crystal structures. We will highlight how structural information can contribute to our understanding of the interactions between the RdRp and viral or host factors.
Language	English
Publishing date	2020-02-25
Publishing country	France
Document type	Journal Article
ISSN	1267-8694
ISSN	1267-8694
DOI	10.1684/vir.2016.0671
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Article: Neuropsychiatric disturbances in presumed late-onset cobalamin C disease.

Roze, Emmanuel / Gervais, David / Demeret, Sophie / Ogier de Baulny, Hélène / Zittoun, Jacqueline / Benoist, Jean-François / Said, Gérard / Pierrot-Deseilligny, Charles / Bolgert, Francis

Archives of neurology

2003 Volume 60, Issue 10, Page(s) 1457–1462

Abstract: Background: Combined methylmalonic aciduria and homocystinuria cobalamin C type (cobalamin C ... cobalamin C disease.: Design: Case report and review of the literature.: Setting: Neurological ... due to presumed cobalamin C disease. A 16-year-old girl was initially seen with psychosis and severe ...

Abstract	Background: Combined methylmalonic aciduria and homocystinuria cobalamin C type (cobalamin C disease) is an inborn metabolic disorder consisting of an impaired intracellular synthesis of the 2 active forms of vitamin B12 (cobalamin), namely, adenosylcobalamin and methylcobalamin, that results in increased levels of methylmalonic acid and homocysteine in the blood and urine. Most patients present in the first year of life with systemic, hematological, and neurological abnormalities. Late-onset forms are rare and had not been comprehensively characterized. They could be easily misdiagnosed. Objective: To describe clinical and biochemical features of the disease in 2 siblings affected with presumed late-onset cobalamin C disease. Design: Case report and review of the literature. Setting: Neurological intensive care unit of a university hospital. Observation: We describe 2 patients with neurological deterioration due to presumed cobalamin C disease. A 16-year-old girl was initially seen with psychosis and severe progressive neuropathy requiring mechanical ventilatory support and her 24-year-old sister had a 2-year disease course of subacute combined degeneration of the spinal cord. A metabolic workup displayed increased methylmalonic acid levels, severe hyperhomocysteinemia, and low plasma methionine levels. The diagnosis was then confirmed by demonstration of impaired synthesis of adenosylcobalamin and methylcobalamin in cultured skin fibroblasts and Epstein-Barr virus-infected lymphocytes. Under specific treatment the younger sister's condition dramatically improved. Conclusions: Although complementation studies have not been conducted, it is most likely these patients had cobalamin C disease. This study emphasizes the possibility of late-onset disease with purely neurological manifestations. Left untreated, this treatable condition can lead to death or irreversible damage to the nervous system. Screening for intracellular vitamin B12 dysmetabolism should, therefore, be considered in the investigation of adults with unexplained neurological disease, particularly when they are initially seen with a clinical picture suggestive of vitamin B12 deficiency.
MeSH term(s)	Adolescent ; Adult ; Brain/pathology ; Cobamides/metabolism ; Female ; Fibroblasts/metabolism ; Homocysteine/blood ; Homocysteine/urine ; Humans ; Mental Disorders/etiology ; Mental Disorders/pathology ; Mental Disorders/psychology ; Metabolism, Inborn Errors/complications ; Metabolism, Inborn Errors/metabolism ; Metabolism, Inborn Errors/psychology ; Methylmalonic Acid/blood ; Methylmalonic Acid/urine ; Nervous System Diseases/etiology ; Nervous System Diseases/pathology ; Nervous System Diseases/psychology ; Sural Nerve/pathology ; Vitamin B 12/analogs & derivatives ; Vitamin B 12/metabolism
Chemical Substances	Cobamides ; Homocysteine (0LVT1QZ0BA) ; Methylmalonic Acid (8LL8S712J7) ; mecobalamin (BR1SN1JS2W) ; cobamamide (F0R1QK73KB) ; Vitamin B 12 (P6YC3EG204)
Language	English
Publishing date	2003-10
Publishing country	United States
Document type	Clinical Trial ; Journal Article
ZDB-ID	80049-1
ISSN	1538-3687 ; 0003-9942
ISSN (online)	1538-3687
ISSN	0003-9942
DOI	10.1001/archneur.60.10.1457
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Article: Bedside video-oculography to assess the caloric vestibulo-ocular reflex in ICU patients, a preliminary study.

Marois, C / Quirins, M / Seassau, M / Demeret, S / Demoule, A / Naccache, L / Weiss, N

Revue neurologique

2023 Volume 179, Issue 9, Page(s) 1030–1034

MeSH term(s)	Humans ; Reflex, Vestibulo-Ocular ; Eye Movements ; Intensive Care Units
Language	English
Publishing date	2023-07-19
Publishing country	France
Document type	Journal Article
ZDB-ID	4593-7
ISSN	2213-0004 ; 0035-3787
ISSN (online)	2213-0004
ISSN	0035-3787
DOI	10.1016/j.neurol.2023.02.069
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Article: Risk factors and prognosis of orotracheal intubation in aquaporin-4-IgG neuromyelitis optica spectrum disorder attacks.

Januel, Edouard / Brochard, Vincent / Le Guennec, Loïc / Maillart, Elisabeth / Louapre, Céline / Lubetzki, Catherine / Weiss, Nicolas / Demeret, Sophie / Papeix, Caroline

Annals of intensive care

2024 Volume 14, Issue 1, Page(s) 4

Abstract: Background: Aquaporin-4 immunoglobulin G Neuro Myelitis Optica spectrum disorders attacks (NMOSD-AQP4-IgG+ attacks) can cause respiratory failure requiring orotracheal intubation (OTI), but the risk factors and outcomes of OTI during attacks remain ... ...

Abstract	Background: Aquaporin-4 immunoglobulin G Neuro Myelitis Optica spectrum disorders attacks (NMOSD-AQP4-IgG+ attacks) can cause respiratory failure requiring orotracheal intubation (OTI), but the risk factors and outcomes of OTI during attacks remain unclear. Our primary objective was to identify the clinical and radiological risk factors for OTI in NMOSD-AQP4-IgG+ attacks. As a secondary objective, we aimed to evaluate the prognosis of OTI-attacks. Methods: We retrospectively analyzed NMOSD-AQP4-IgG+ attacks at the Pitié-Salpêtrière Hospital (Jan 2010-Jan 2021), excluding isolated optic neuritis. The primary outcome was the need for OTI due to neurological dysfunction an attack (OTI-attack). The secondary outcome was attack's poor recovery after 12 months, defined as a modified Rankin score (mRS) > 2 in patients with an initial mRS ≤ 2, or an increase ≥ 1 point in mRS in other patients. Analyses were performed using a binomial generalized linear mixed model, with a random intercept for the patient ID to account for within-patient correlations. Results: Seventy-three attacks in 44 patients NMOSD-AQP4-IgG+ were analyzed. Of 73 attacks, 8 (11%) required OTI during the attack, related to acute restrictive respiratory failure (n = 7) and/or severe swallowing disorder (n = 2). None of the OTI-attacks occurred in patients previously treated with active disease-modifying treatment (DMT), while 36 (55.4%) of the non-OTI-attacks occurred in patients who were already on active DMT. On admission, OTI-attacks were more likely to have upper limbs motor paresis of (75.0% versus 29.2%, p = 0.366) and dyspnea (3 [50.0%] versus 4 [6.6%], p = 0.002) compared to non-OTI-attacks. MRI analysis showed that OTI-attacks had edematous lesions in the cervical spinal cord, mainly at levels C1 (75% versus 0% in non-OTI-attacks), C2 (75% versus 1.9%), C3 (62.5% versus 1.9%), and C4 and C5 levels (50% versus to 3.9%). One OTI-attack resulted in the death of one patient. Five patients with OTI-attack had mRS ≤ 2 one year after OTI-attack. Two (25%) OTI-attacks had poor recovery compared to 15 (24.2%) non-OTI-attacks (p = 0.468). Conclusion: OTI-attacks occurred in untreated NMOSD-AQP4-IgG+ patients and were associated with edematous upper cervical lesions. The prognosis of these attacks may be favorable, and warrant maximal medical and supportive treatment. Trial registration This was a retrospective observational monocentric cohort study nested in the NOMADMUS cohort (ClinicalTrials.gov Identifier: NCT02850705).
Language	English
Publishing date	2024-01-08
Publishing country	Germany
Document type	Journal Article
ZDB-ID	2617094-2
ISSN	2110-5820
ISSN	2110-5820
DOI	10.1186/s13613-023-01213-x
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Article: Toxic-metabolic encephalopathy in adults: Critical discussion and pragmatical diagnostic approach.

Le Guennec, L / Marois, C / Demeret, S / Wijdicks, E F M / Weiss, N

Revue neurologique

2022 Volume 178, Issue 1-2, Page(s) 93–104

Abstract: Toxic-metabolic encephalopathy (TME) results from an acute cerebral dysfunction due to different metabolic disturbances including medications or illicit-drugs. It can lead to altered consciousness, going from delirium to coma, which may require intensive ...

Abstract	Toxic-metabolic encephalopathy (TME) results from an acute cerebral dysfunction due to different metabolic disturbances including medications or illicit-drugs. It can lead to altered consciousness, going from delirium to coma, which may require intensive care and invasive mechanical ventilation. Even if it is a life-threatening condition, TME might have an excellent prognosis if its etiology is rapidly identified and treated adequately. This review summarizes the main etiologies, their differential diagnosis, and diagnostic strategy and management of TME with a critical discussion on the definition of TME.
MeSH term(s)	Brain Diseases/diagnosis ; Brain Diseases/etiology ; Brain Diseases, Metabolic/diagnosis ; Brain Diseases, Metabolic/etiology ; Coma/diagnosis ; Coma/etiology ; Critical Care ; Humans ; Intensive Care Units ; Respiration, Artificial
Language	English
Publishing date	2022-01-04
Publishing country	France
Document type	Journal Article ; Review
ZDB-ID	4593-7
ISSN	2213-0004 ; 0035-3787
ISSN (online)	2213-0004
ISSN	0035-3787
DOI	10.1016/j.neurol.2021.11.007
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