The Role of the Ubiquitin–Proteasome Pathway in the Formation of Mallory Bodies

Bardag‐Gorce, Fawzia; Leeuwen, F.W. van; Nguyen, Victoria; French, Barbara A.; Li, Jun; Riley, Nora E.; McPhaul, Laron; Lue, Yanhe; French, Samuel W.

doi:10.1006/exmp.2002.2451

Cited by 50 publications

(24 citation statements)

References 29 publications

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“…Similarly, in liver tissue, the formation of Mallory bodies, which are composed of hyperphosphorylated and ubiquitylated keratin, is also associated with impairment of the proteasome (Bardag-Gorce et al, 2002;Riley et al, 2002). It is possible that levels of ubiquitylated keratin eventually exceed the capacity of the proteasome, resulting in a general impairment of the ubiquitin-proteasome system, allowing reaccumulation of keratin.…”

Section: Discussionmentioning

confidence: 99%

E1^E4-mediated keratin phosphorylation and ubiquitylation: a mechanism for keratin depletion in HPV16-infected epithelium

McIntosh¹,

Laskey²,

Sullivan³

et al. 2010

Journal of Cell Science

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SummaryThe keratin IF network of epidermal keratinocytes provides a protective barrier against mechanical insult, it is also a major player in absorbing stress in these cells. The human papilloma virus (HPV) type 16 E1^E4 protein accumulates in the upper layers of HPV16-infected epithelium and is known to associate with and reorganise the keratin IF network in cells in culture. Here, we show that this function is conserved amongst a number of HPV alpha-group E1^E4 proteins and that the differentiation-dependent keratins are also targeted. Using time-lapse microscopy, HPV16 E1^E4 was found to effect a dramatic cessation of keratin IF network dynamics by associating with both soluble and insoluble keratin. Network disruption was accompanied by keratin hyperphosphorylation at several sites, including K8 S73, which is typically phosphorylated in response to stress stimuli. Keratin immunoprecipitated from E1^E4-expressing cells was also found to be ubiquitylated, indicating that it is targeted for proteasomal degradation. Interestingly, the accumulation of hyperphosphorylated, ubiquitylated E1^E4-keratin structures was found to result in an impairment of proteasomal function. These observations shed new light on the mechanism of keratin IF network reorganisation mediated by HPV16 E1^E4 and provide an insight into the depletion of keratin co-incident with E1^E4 accumulation observed in HPV-infected epithelium.

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Section: Discussionmentioning

confidence: 99%

E1^E4-mediated keratin phosphorylation and ubiquitylation: a mechanism for keratin depletion in HPV16-infected epithelium

McIntosh¹,

Laskey²,

Sullivan³

et al. 2010

Journal of Cell Science

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“…These data suggest that the heart may exhibit an immunoactive phenotype, which is reminiscent of what was reported in the liver and spleen, but in contrast to erythrocytes where inducible subunits in normal cells were not reported. 31,35 A previous report found no inducible subunits in normal rat hearts. 36 The N-terminal peptides of ␤1, ␤2, and ␤5i were found to be free of modification ( Table 1).…”

Section: Molecular Composition Of Murine Cardiac Proteasomesmentioning

confidence: 91%

Mapping the Murine Cardiac 26S Proteasome Complexes

Gomes

Zong

Edmondson

et al. 2006

Circulation Research

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169

188

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Abstract-The importance of proteasomes in governing the intracellular protein degradation process has been increasingly recognized. Recent investigations indicate that proteasome complexes may exist in a species-and cell-type-specific fashion. To date, despite evidence linking impaired protein degradation to cardiac disease phenotypes, virtually nothing is known regarding the molecular composition, function, or regulation of cardiac proteasomes. We have taken a functional proteomic approach to characterize 26S proteasomes in the murine heart. Multidimensional chromatography was used to obtain highly purified and functionally viable cardiac 20S and 19S proteasome complexes, which were subjected to electrophoresis and tandem mass spectrometry analyses. Our data revealed complex molecular organization of cardiac 26S proteasomes, some of which are similar to what were reported in yeast, whereas others exhibit contrasting features that have not been previously identified in other species or cell types. At least 36 distinct subunits (17 of 20S and 19 of 19S) are coexpressed and assembled as 26S proteasomes in this vital cardiac organelle, whereas the expression of PA200 and 11S subunits were detected with limited participation in the 26S complexes. The 19S subunits included a new alternatively spliced isoform of Rpn10 (Rpn10b) along with its primary isoform (Rpn10a). Immunoblotting and immunocytochemistry verified the expression of key ␣ and ␤ subunits in cardiomyocytes. The expression of 14 constitutive ␣ and ␤ subunits in parallel with their three inducible subunits (␤1i, ␤2i, and ␤5i) in the normal heart was not expected; these findings represent a distinct level of structural complexity of cardiac proteasomes, significantly different from that of yeast and human erythrocytes. Furthermore, liquid chromatography/tandem mass spectroscopy characterized 3 distinct types of post-translational modifications including (1) N-terminal acetylation of 19S subunits (Rpn1, Rpn5, Rpn6, Rpt3, and Rpt6) and 20S subunits (␣2, ␣5, ␣7, ␤3, and ␤4); (2) N-terminal myristoylation of a 19S subunit (Rpt2); and (3) phosphorylation of 20S subunits (eg, ␣7)). Taken together, this report presents the first comprehensive characterization of cardiac 26S proteasomes, providing critical structural and proteomic information fundamental to our future understanding of this essential protein degradation system in the normal and diseased myocardium. T he proteasome is a key proteolytic enzymatic system governing the degradation of majority intracellular proteins. 1 Recent studies implicate proteasomes in cardiac diseases. [2][3][4][5][6][7][8][9][10][11] Proteasome inhibitors are widely used in cancer therapy, however, their impact on cardiac function remains unclear; investigations in the heart have reported conflicting results. 2-4,12 A major contributing factor to these controversies is the lack of information pertaining to the structural organization and protein composition of cardiac proteasomes, therefore prohibiting the identification of mol...

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“…5 Also, hepatocytes from alcoholics contain large amounts of ubiquitin in the form of cellular inclusions or Mallory bodies, which accumulate because they are not efficiently degraded by the proteasome. 6 Recent studies have shown that the formation of Mallory bodies that result from inhibiting or overwhelming the ubiquitin-proteasome system is a common pathway of liver injury caused by diverse toxins, including alcohol. 2,4,7 Chronic ethanol consumption causes increased oxidative damage due, in part, to induction of CYP2E1 in the liver.…”

mentioning

confidence: 99%