FAT10 knock out mice livers fail to develop Mallory–Denk bodies in the DDC mouse model

French, Samuel W.; French, Barbara A.; Oliva, Joan; Li, J.; Bardag‐Gorce, Fawzia; Tillman, Brittany; Canaan, Allon

doi:10.1016/j.yexmp.2012.09.002

Cited by 25 publications

(27 citation statements)

References 15 publications

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“…MDB formation may be the result of the reduced activity of the FAT10ylation pathway of protein degradation, causing the proteins to accumulate and form aggresomes (MDBS). The FATylation pathway of protein degradation may be essential for MDB formation, since FAT10 knockout (KO) mice refed DDC failed to form MDBs compared with wild-type mice refed DDC where numerous MDBs were formed [4]. …”

Section: Role Of the Ufmylation And Fat10ylation Pathways To Protementioning

confidence: 99%

Role of Protein Quality Control Failure in Alcoholic Hepatitis Pathogenesis

et al. 2017

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The mechanisms of protein quality control in hepatocytes in cases of alcoholic hepatitis (AH) including ufmylation, FAT10ylation, metacaspase 1 (Mca1), ERAD (endoplasmic reticulum-associated degradation), JUNQ (juxta nuclear quality control), IPOD (insoluble protein deposit) autophagocytosis, and ER stress are reviewed. The Mallory–Denk body (MDB) formation develops in the hepatocytes in alcoholic hepatitis as a consequence of the failure of these protein quality control mechanisms to remove misfolded and damaged proteins and to prevent MDB aggresome formation within the cytoplasm of hepatocytes. The proteins involved in the quality control pathways are identified, quantitated, and visualized by immunofluorescent antibody staining of liver biopsies from patients with AH. Quantification of the proteins are achieved by measuring the fluorescent intensity using a morphometric system. Ufmylation and FAT10ylation pathways were downregulated, Mca1 pathways were upregulated, autophagocytosis was upregulated, and ER stress PERK (protein kinase RNA-like endoplasmic reticulum kinase) and CHOP (CCAAT/enhancer-binding protein homologous protein) mechanisms were upregulated. In conclusion: Despite the upregulation of several pathways of protein quality control, aggresomes (MDBs) still formed in the hepatocytes in AH. The pathogenesis of AH is due to the failure of protein quality control, which causes balloon-cell change with MDB formation and ER stress.

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Section: Role Of the Ufmylation And Fat10ylation Pathways To Protementioning

confidence: 99%

Role of Protein Quality Control Failure in Alcoholic Hepatitis Pathogenesis

et al. 2017

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“…It has been demonstrated that the autophagosomal receptor p62/SQSTM1 becomes covalently mono-FAT10ylated at several lysines, and that FAT10 co-localizes with p62 in p62 bodies . Furthermore, FAT10 is involved in the formation of Mallory-Denk bodies, which are aggresome-like structures in hepatocellular carcinoma cells composed of ubiquitylated proteins (French et al, 2012). Additionally, FAT10 decorates autophagy-targeted Salmonella and contributes to Salmonella resistance in mice (Spinnenhirn et al, 2014) (see below).…”

Section: Fat10 In Antigen Processingmentioning

confidence: 99%

The ubiquitin-like modifier FAT10 in antigen processing and antimicrobial defense

Basler

Buerger

Groettrup

2015

Molecular Immunology

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a b s t r a c tThe ubiquitin-like modifier (ULM) HLA-F adjacent transcript 10 (FAT10) is encoded in the MHC locus, is up-regulated during dendritic cell maturation, is highly expressed in lymphoid tissues, and strongly induced by interferon (IFN)-␥ and tumor necrosis factor (TNF)-␣. FAT10 is the only ULM known to date which directly targets its hundreds of substrates for degradation by the proteasome. This implies a role for FAT10 in antigen presentation. Indeed, fusion of FAT10 to viral proteins enhanced their presentation along the proteasome dependent MHC class I presentation pathway. In this review we discuss the FAT10 conjugation system as an alternative and distinct pathway for MHC class I and II antigen processing. Furthermore, we review the recent finding that FAT10 plays a role in antimicrobial defense against intracellular pathogens.

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“…3,5 UbD 2/2 mice fed DDC cannot form MDBs. 6 SAMUEL FRENCH, M.D. Harbor-UCLA Medical Center Torrance, CA…”

Section: Hepatocyte Levels Of Cd73 Contribute To Mallory-denk Body Fomentioning

confidence: 99%

Reply

Hsu

Chen²,

Cheng³

2014

Hepatology

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in patients with resolved HBV infection, 1,4,5 but a standard management according to the risk of HBV reactivation has not been established as yet. We hope that the additional information can help readers regarding the optimal interval and sensitivity of the HBV DNA monitoring assay. In addition, if the reappearance of HBsAg and viral mutations related to viral replication are good predictive markers for severe hepatitis resulting from HBV reactivation, we can recommend that antiviral treatment should be started immediately for those patients with HBV reactivation. Reply:We thank Dr. Kusumoto and his colleagues for their comments on our study. 1 Management of chemotherapy-induced hepatitis B virus (HBV) reactivation in lymphoma patients with resolved HBV infection is a challenging issue in endemic areas because 50%-60% of the general population in those areas have resolved HBV infection, and the clinical courses of HBV reactivation in this patient population vary greatly. Dr. Kusumoto pointed out several important points that warrant further investigation.With increasing sensitivity of the HBV DNA tests, chemotherapy-induced HBV reactivation can be detected in about 20% of lymphoma patients who receive rituximab/CHOP chemotherapy and can be detected earlier (median, 11.8 weeks earlier than the less-sensitive assay). 1,2 However, in our study, most of the additional HBV reactivations detected by the more-sensitive assay were asymptomatic. Only 1 patient had a hepatitis flare, which resolved spontaneously. It is difficult to analyze whether earlier use of antiviral therapy by a more-sensitive assay can further reduce the number of HBV-related hepatitis flares, given the small number of patients. Therefore, the clinical benefit of HBV reactivation detected by the more-sensitive assay for pre-emptive antivirals remains to be established.Reappearance of hepatitis B surface antigen (HBsAg), which can be measured conveniently in the clinic by chemiluminescent immunoassay, such as the Abbott Architect assay (Abbott Laboratories, Abbott Park, IL), was found, in our study, to be significantly associated with HBV-related hepatitis flares. The sensitivity of HBsAg tests currently used in the clinic can be as low as 0.05 IU/mL. Most of the patients were found to be HBsAg 1 at the time of hepatitis flare. Therefore an assay for HBsAg during the chemotherapy course is strongly advocated, in addition to HBV DNA. Whether HBsAg assay is useful, and more cost-effective for managing HBV reactivations in lymphoma patients, warrants a prospective study. Finally, we agree with Dr. Kusumoto that persistence of HBsAg positivity for more than 6 months may negatively influence long-term outcome, and long-term follow-up of patients with reappearance of HBsAg is ongoing.Dr. Kusumoto pointed out the potential importance of viral factors, including the HBV replication levels and the presence of precore/basal core promoter mutations, in the development of severe hepatitis flare. Because the majority of the patients did not have detectable HBV...

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FAT10 knock out mice livers fail to develop Mallory–Denk bodies in the DDC mouse model

Cited by 25 publications

References 15 publications

Role of Protein Quality Control Failure in Alcoholic Hepatitis Pathogenesis

Role of Protein Quality Control Failure in Alcoholic Hepatitis Pathogenesis

The ubiquitin-like modifier FAT10 in antigen processing and antimicrobial defense

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