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© The Rockefeller University Press, 0021-9525/1999//481 $5.00
The Journal of Cell Biology, Volume 145, Number 3, , 1999 481-490

Regular Articles

Dynamic Association of Proteasomal Machinery with the Centrosome



W. Christian Wigley*, Rosalind P. Fabunmi*, Min Goo Lee{ddagger}, Christopher R. Marino§, Shmuel Muallem*, George N. DeMartino*, and Philip J. Thomas*

* Department of Physiology, The University of Texas Southwestern Medical Center, Dallas, Texas 75235; {ddagger} 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

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 {gamma}-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.

Key Words: proteasome • protein misfolding • inclusions • CFTR • centrosome

Abbreviations used in this paper: 20S, 20S proteasome; cAMP, adenosine 3',5'-cyclic monophosphate; CF, cystic fibrosis; CFTR, cystic fibrosis transmembrane conductance regulator; Hsp70/Hsp90, heat shock protein (70 and 90 kD, respectively); NBD, nucleotide binding domain; PA700/ PA28, proteasome activator complex (700 and 180 kD, respectively); PKA, cAMP-dependent protein kinase; SCA1, type-1 spinocerebellar ataxia; TMD, transmembrane domain; Ub, ubiquitin; TBS-T, tris-buffered saline/0.1% Tween-20.


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