Wilhelm bernhard workshop on the cell nucleus

AGGRESOME-LIKE INCLUSIONS WITHIN THE NUCLEOPLASM:

PROTEASOMAL DEGRADATION AND SUB-NUCLEAR PATHOLOGY

Chen M., Rockel T., Hemmerich P., and von Mikecz A.

Insitut für umweltmedizinische Forschung (IUF), Heinrich-Heine-University Düsseldorf, Germany
Protein aggregates and inclusions containing a variety of cellular proteins such as ubiquitin, proteasomes, heat shock proteins, and transcriptional coactivator CBP are hallmarks of neurodegenerative diseases. Studies on the composition and dynamics of such aggregates have led to an intriguing new hypothesis for disease, namely, that the sequestration of certain essential cellular proteins by protein aggregates results in a loss-of-function phenotype and ultimately in tissue dysgenesis. We reported previously that (1) proteasomal degradation of nuclear proteins is correlated with their subnuclear localization (J. Struct. Biol. 140: 189, 2002), and (2) recruitment of the nucleolar autoantigen fibrillarin to proteasome-dependent degradation occurs upon xenobiotic-induction in cell culture and animal models (Mol. Biol. Cell 13:3576, 2002). Quantification of fluorescence intensities and measurement of proteasomal activity in nuclear fractions corroborate that nuclear proteins that colocalize with proteasomes are degraded by proteasome-dependent proteolysis within the nucleoplasm. Moreover, upon induction by certain xenobiotics protein aggregates are formed in the nucleoplasm that contain proteasomes, topoisomerase I, fibrillarin, spliceosomal components, PML, and CBP. We term these aggregates aggresome-like inclusions (ALIs). The formation of ALIs correlates with decreased replication, and transcription activity and results in arrest of cell growth. Since ALIs are detectable in primary cells from patients with systemic autoimmune diseases we suggest that ALI formation represents a novel subnuclear pathology.