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J. Cell Biol.,
Volume 145, Number 3, May 3, 1999 481-490
* Department of Physiology, The University of Texas Southwestern Medical Center, Dallas, Texas 75235; Although the number of pathologies known
to arise from the inappropriate folding of proteins continues to grow, mechanisms underlying the recognition
and ultimate disposition of misfolded polypeptides remain obscure. For example, how and where such substrates are identified and processed is unknown. We report here the identification of a specific subcellular
structure in which, under basal conditions, the 20S proteasome, the PA700 and PA28 (700- and 180-kD proteasome activator complexes, respectively), ubiquitin,
Hsp70 and Hsp90 (70- and 90-kD heat shock protein,
respectively) concentrate in HEK 293 and HeLa cells.
The structure is perinuclear, surrounded by endoplasmic reticulum, adjacent to the Golgi, and colocalizes with The Department
of Pharmacology, Yonsei University College of Medicine, Seoul 120-752, Korea; and the § Department of Medicine and
Physiology, University of Tennessee, Memphis, Tennessee 38163
-tubulin, an established centrosomal marker.
Density gradient fractions containing purified centrosomes are enriched in proteasomal components and
cell stress chaperones. The centrosome-associated structure enlarges in response to inhibition of proteasome activity and the level of misfolded proteins. For
example, folding mutants of CFTR form large inclusions which arise from the centrosome upon inhibition
of proteasome activity. At high levels of misfolded protein, the structure not only expands but also extensively
recruits the cytosolic pools of ubiquitin, Hsp70, PA700,
PA28, and the 20S proteasome. Thus, the centrosome
may act as a scaffold, which concentrates and recruits
the systems which act as censors and modulators of the
balance between folding, aggregation, and degradation.
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