title: p62/Sequestosome-1 Is Indispensable for Maturation and Stabilization of Mallory-Denk Bodies.
abstract: Mallory-Denk bodies (MDBs) are hepatocytic protein aggregates found in steatohepatitis and several other chronic liver diseases as well as hepatocellular carcinoma. MDBs are mainly composed of phosphorylated keratins and stress protein p62/Sequestosome-1 (p62), which is a common component of cytoplasmic aggregates in a variety of protein aggregation diseases. In contrast to the well-established role of keratins, the role of p62 in MDB pathogenesis is still elusive. We have generated total and hepatocyte-specific p62 knockout mice, fed them with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) to induce MDBs and allowed the mice to recover from DDC intoxication on a standard diet to investigate the role of p62 in MDB formation and elimination. In the absence of p62, smaller, granular and less distinct MDBs appeared, which failed to mature to larger and compact inclusions. Moreover, p62 deficiency impaired the binding of other proteins such as NBR1 and Hsp25 to MDBs and altered the cellular defense mechanism by downregulation of Nrf2 target genes. Upon recovery from DDC intoxication on a standard diet, there was an enhanced reduction of p62-deficient MDBs, which was accompanied by a pronounced decrease in ubiquitinated proteins. Our data provide strong evidence that keratin aggregation is the initial step in MDB formation in steatohepatitis-related mouse models. Interaction of p62 with keratin aggregates then leads to maturation i.e., enlargement and stabilization of the MDBs as well as recruitment of other MDB-associated proteins.
authors.affiliation: Institute of Pathology, Medical University of Graz, Graz, Austria.
authors.forename: Pooja
authors.initials: P
authors.lastname: Lahiri
authors.affiliation: Institute of Laboratory Animal Science, University of Veterinary Medicine Vienna, Vienna, Austria.
authors.forename: Volker
authors.initials: V
authors.lastname: Schmidt
authors.affiliation: Institute of Pathology, Medical University of Graz, Graz, Austria.
authors.forename: Claudia
authors.initials: C
authors.lastname: Smole
authors.affiliation: Institute of Pathology, Medical University of Graz, Graz, Austria.
authors.forename: Iris
authors.initials: I
authors.lastname: Kufferath
authors.affiliation: Institute of Pathology, Medical University of Graz, Graz, Austria.
authors.forename: Helmut
authors.initials: H
authors.lastname: Denk
authors.affiliation: IZKF and Department of Internal Medicine III, Aachen, Germany.
authors.forename: Pavel
authors.initials: P
authors.lastname: Strnad
authors.affiliation: Institute of Laboratory Animal Science, University of Veterinary Medicine Vienna, Vienna, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Rülicke
authors.affiliation: Institute of Pathology, Medical University of Graz, Graz, Austria.
authors.forename: Leopold F
authors.initials: LF
authors.lastname: Fröhlich
authors.affiliation: Institute of Pathology, Medical University of Graz, Graz, Austria.
authors.forename: Kurt
authors.initials: K
authors.lastname: Zatloukal
mesh_terms: D000818:Animals; D055786:Gene Knockout Techniques; D022781:Hepatocytes / Q000166:cytology; D047908:Intracellular Signaling Peptides and Proteins; D059609:Mallory Bodies / Q000378:metabolism*; D051379:Mice; D011506:Proteins / Q000378:metabolism; D000071456:Sequestosome-1 Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C486326:Nbr1 protein, mouse; D011506:Proteins; D000071456:Sequestosome-1 Protein