MALLORY BODY FILAMENTS BECOME INSOLUBLE AFTER NORMAL ASSEMBLY INTO INTERMEDIATE FILAMENTS

The deposition of 8-to-10-nm filaments into inclusion bodies is a fund amental cellular change that occurs in several degenerative processes of many tissues. However, little is known about the pathological filam ents including whether the filaments assemble by the same mechanisms t hat govern the assembly of normal intermediate filaments. We have addr essed this issue by studying the in vitro reassembly of the cytokerati n filaments that are deposited into experimental murine Mallory bodies (MBs) but have not yet become covalently crosslinked components of th e MB. The reassembly process of both normal hepatocellular and MB-deri ved cytokeratins (CKs) was similar and characterized by a hierarchy of protofilament and protofibrils with a prominent axial periodicity of similar to 21 nm (normal hepatocellular CK, 20.7 +/- 2 nm; MB-derived CK, 20.1 +/- 2 nm). Purified MB-derived CK and normal hepatocellular C K comigrated in polyacrylamide gel electrophoresis indicating composit ion by similar CK isoforms. These results indicate that intermediate f ilaments formed from MB-derived CK are indistinguishable from filament s assembled from normal CK. On this basis, we conclude that the interm ediate filaments that form inclusion bodies are not aberrantly assembl ed but become aggregated and post-translationally modified after their initial formation.