<scp>MID</scp>2 can substitute for <scp>MID</scp>1 and control exocytosis of lytic granules in cytotoxic T cells

Boding, Lasse; Hansen, Anker; Meroni, Germana; Levring, Trine B.; Woetmann, Anders; Ødum, Niels; Bonefeld, Charlotte M.; Geisler, Carsten

doi:10.1111/apm.12402

Cited by 4 publications

(4 citation statements)

References 27 publications

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“…Circulating proteolytically active GZMA would appear to have limited influence in the spleen as only four DEGs were identified in the spleen of poly(I:C)-treated Gzma S211A vs. 6J mice ( Supplementary file 6d ). Interestingly, the only significantly upregulated DEG in Gzma S211A spleens was Mid1, a gene involved in controlling granule exocytosis by cytotoxic lymphocytes ( Boding et al, 2014 ; Boding et al, 2015 ). GSEA also illustrated that neither up- nor downregulated DEGs identified in the feet were enriched in spleen ( Figure 6—figure supplement 3 ), arguing that in this setting the activity of GZMA in the periphery is not significantly recapitulated in spleen.…”

Section: Resultsmentioning

confidence: 99%

Widespread discrepancy in Nnt genotypes and genetic backgrounds complicates granzyme A and other knockout mouse studies

Rawle

Dumenil

et al. 2022

eLife

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Granzyme A (GZMA) is a serine protease secreted by cytotoxic lymphocytes, with Gzma-/- mouse studies having informed our understanding of GZMA’s physiological function. We show herein that Gzma-/- mice have a mixed C57BL/6J and C57BL/6N genetic background and retain the full-length nicotinamide nucleotide transhydrogenase (Nnt) gene, whereas Nnt is truncated in C57BL/6J mice. Chikungunya viral arthritis was substantially ameliorated in Gzma-/- mice; however, the presence of Nnt and the C57BL/6N background, rather than loss of GZMA expression, was responsible for this phenotype. A new CRISPR active site mutant C57BL/6J GzmaS211A mouse provided the first insights into GZMA’s bioactivity free of background issues, with circulating proteolytically active GZMA promoting immune-stimulating and pro-inflammatory signatures. Remarkably, k-mer mining of the Sequence Read Archive illustrated that ≈27% of Run Accessions and ≈38% of BioProjects listing C57BL/6J as the mouse strain had Nnt sequencing reads inconsistent with a C57BL/6J genetic background. Nnt and C57BL/6N background issues have clearly complicated our understanding of GZMA and may similarly have influenced studies across a broad range of fields.

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Section: Resultsmentioning

confidence: 99%

Widespread discrepancy in Nnt genotypes and genetic backgrounds complicates granzyme A and other knockout mouse studies

Rawle

Dumenil

et al. 2022

eLife

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“…BOLA class I, the most up-regulated target in transitional terminators is one of the proteins most intrinsically associated with induction of cell mediated immunity 25 . Also among the most highly overexpressed targets, midline 2 (MID2, also known as TRIM1) is a ubiquitin ligase that is critically involved in cytotoxic granule exocytosis in CD8 T cells by regulation of the microtubule framework 26 . Additional overexpressed targets included basic helix-loop-helix family member e40 (BHLHE40) which is a transcription factor that is induced by IL-1β.…”

Section: Resultsmentioning

confidence: 99%

Clearance of a persistent picornavirus infection is associated with enhanced pro-apoptotic and cellular immune responses

Stenfeldt

Eschbaumer

Smoliga

et al. 2017

Sci Rep

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Long-term persistent viral infections cause substantial morbidity and associated economic losses in human and veterinary contexts. Yet, the mechanisms associated with establishment of persistent infections are poorly elucidated. We investigated immunomodulatory mechanisms associated with clearance versus persistence of foot-and-mouth disease virus (FMDV) in micro-dissected compartments of the bovine nasopharynx by microarray. The use of laser-capture microdissection allowed elucidation of differential gene regulation within distinct anatomic compartments critical to FMDV infection. Analysis of samples from transitional and persistent phases of infection demonstrated significant differences in transcriptome profiles of animals that cleared infection versus those that became persistently infected carriers. Specifically, it was demonstrated that clearance of FMDV from the nasopharyngeal mucosa was associated with upregulation of targets associated with activation of T cell-mediated immunity. Contrastingly, gene regulation in FMDV carriers suggested inhibition of T cell activation and promotion of Th2 polarization. These findings were corroborated by immunofluorescence microscopy which demonstrated relative abundance of CD8 + T cells in the nasopharyngeal mucosa in association with clearance of FMDV. The findings presented herein emphasize that a critical balance between Th1 and Th2 -mediated immunity is essential for successful clearance of FMDV infection and should be considered for development of next-generation vaccines and antiviral products.Foot-and-mouth disease virus (FMDV), the prototype Aphthovirus within the Picornaviridae family, is the causal agent of foot-and-mouth disease (FMD), a highly contagious disease of cloven-hoofed animals 1 . The endemic presence of FMD in large regions of the world compromises food security and animal welfare. Additionally, as a country's official FMD status defines access to international markets for export of animal products, this disease has a substantial global economic impact on agricultural production and trade.Control and eradication of FMD is impeded by the existence of a prolonged subclinical persistent phase of infection in ruminant species 2-4 . This concept, generally referred to as the FMDV carrier state, is specifically problematic when vaccination is used to control FMD in non-endemic regions as vaccinated cattle may maintain subclinical FMDV persistence following virus exposure, despite having been protected against the clinical disease 5-12 . Confirmed evidence of FMDV transmission from persistently infected cattle is lacking. However, because infectious FMDV is detectable in oropharyngeal fluid (OPF) and nasopharyngeal tissues of carriers for prolonged periods of time, the presence of such animals precludes achieving an official status as FMD-free by the international organization for animal health (OIE) 13 .In cattle, persistent FMDV has been localized to the follicle-associated epithelium (FAE) of the nasopharyngeal mucosa 10,11 or associated lymph nodes ...

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“…It can be associated with MID1 gene defects which interacts with MID2 (8), and are implicated in midline anomalies (9, 10). The Toriello Carey syndrome has the co-occurrence of hypospadias and facial anomalies.…”

Section: Discussionmentioning

confidence: 99%

Craniofacial anomalies associated with hypospadias. Description of a hospital based population in South America

2016

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Introduction:Hypospadias is a congenital abnormality of the penis, in which there is incomplete development of the distal urethra. There are numerous reports showing an increase of prevalence of hypospadias. Association of craniofacial malformations in patients diagnosed with hypospadias is rare. The aim of this study is to describe the association between hypospadias and craniofacial congenital anomalies.Materials and Methods:A retrospective review of the Latin-American collaborative study of congenital malformations (ECLAMC) data was performed between January 1982 and December 2011. We included children diagnosed with associated hypospadias and among them we selected those that were associated with any craniofacial congenital anomaly.Results:Global prevalence was 11.3 per 10.000 newborns. In this population a total of 809 patients with 1117 associated anomalies were identified. On average there were 1.7 anomalies per patient. Facial anomalies were present in 13.2%. The most commonly major facial anomaly associated to hypospadias was cleft lip/palate with 52 cases. We identified that 18% have an association with other anomalies, and found an association between craniofacial anomalies and hypospadias in 0.59 cases/10.000 newborns.Discussion:Hypospadias is the most common congenital anomaly affecting the genitals. Its association with other anomalies is rare. It has been reported that other malformations occur in 29.3% of the cases with hypospadias. The more proximal the meatus, the higher the risk for having another associated anomaly.Conclusion:Associated hypospadias are rare, and it is important to identify the concurrent occurrence of craniofacial anomalies to better treat patients that might need a multidisciplinary approach.

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MID2 can substitute for MID1 and control exocytosis of lytic granules in cytotoxic T cells

Cited by 4 publications

References 27 publications

Widespread discrepancy in Nnt genotypes and genetic backgrounds complicates granzyme A and other knockout mouse studies

Widespread discrepancy in Nnt genotypes and genetic backgrounds complicates granzyme A and other knockout mouse studies

Clearance of a persistent picornavirus infection is associated with enhanced pro-apoptotic and cellular immune responses

Craniofacial anomalies associated with hypospadias. Description of a hospital based population in South America

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