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Schematic drawing of the different role of p62 and keratin in two distinct hypothetical pathways of MDB formation.

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posted on 15.08.2016 by Pooja Lahiri, Volker Schmidt, Claudia Smole, Iris Kufferath, Helmut Denk, Pavel Strnad, Thomas Rülicke, Leopold F. Fröhlich, Kurt Zatloukal

(A1) In the first pathway alcohol abuse or metabolic alterations associated with obesity in the context of human alcoholic or non-alcoholic steatohepatitis (ASH or NASH), and DDC or griseofulvin administration in mice trigger the upregulation of keratins (K8 and K18) with, increased K8:K18 ratio and cross β-sheet conformation of K8, which leads to the formation of small ‟early” MDBs with filamentous ultrastructure and MM120-1 antigen positivity. (A2) The coalescence of small MDBs to form large, compact ‟mature” MDBs occurs via incorporation of p62. Binding of p62 to MDBs also promotes the recruitment of NBR1 and other proteins to MDBs. (B1) In the second pathway (found in hepatocellular carcinoma and idiopathic copper toxicosis) p62-containing IHBs, which are negative for keratin and do not show cross β-sheet conformation, may progress to (B2) hybrid inclusions (showing mixed features of both IHBs and MDBs) by incorporation of keratins (K8 and K18). (B3) The hybrid inclusions may transform to ‟mature” MDBs upon further incorporation of K8 and K18.