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J. Biol. Chem., Vol. 283, Issue 41, 27575-27584, October 10, 2008

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Triggering Aggresome Formation

DISSECTING AGGRESOME-TARGETING AND AGGREGATION SIGNALS IN SYNPHILIN 1^*

From the Department of Biochemistry, Boston University Medical School, Boston, Massachusetts 02118

Abnormal polypeptides that escape proteasome-dependent degradation and aggregate in cytosol can be transported via microtubules to an aggresome, a recently discovered organelle where aggregated proteins are stored or degraded by autophagy. We used synphilin 1, a protein implicated in Parkinson disease, as a model to study mechanisms of aggresome formation. When expressed in naïve HEK293 cells, synphilin 1 forms multiple small highly mobile aggregates. However, proteasome or Hsp90 inhibition rapidly triggered their translocation into the aggresome, and surprisingly, this response was independent on the expression level of synphilin 1. Therefore, aggresome formation, but not aggregation of synphilin 1, represents a special cellular response to a failure of the proteasome/chaperone machinery. Importantly, translocation to aggresomes required a special aggresome-targeting signal within the sequence of synphilin 1, an ankyrin-like repeat domain. On the other hand, formation of multiple small aggregates required an entirely different segment within synphilin 1, indicating that aggregation and aggresome formation determinants can be separated genetically. Furthermore, substitution of the ankyrin-like repeat in synphilin 1 with an aggresome-targeting signal from huntingtin was sufficient for aggresome formation upon inhibition of the proteasome. Analogously, attachment of the ankyrin-like repeat to a huntingtin fragment lacking its aggresome-targeting signal promoted its transport to aggresomes. These findings indicate the existence of transferable signals that target aggregation-prone polypeptides to aggresomes.

Received for publication, March 20, 2008 , and in revised form, June 13, 2008.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S5.

¹ To whom correspondence should be addressed: Dept. of Biochemistry, Boston University Medical School, 715 Albany St., K323, Boston, MA 02118. Tel.: 617-638-5971; Fax: 617-638-5339; E-mail: sherma1{at}bu.edu.

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This article has been cited by other articles:

				Y. Wang, A. B. Meriin, N. Zaarur, N. V. Romanova, Y. O. Chernoff, C. E. Costello, and M. Y. Sherman Abnormal proteins can form aggresome in yeast: aggresome-targeting signals and components of the machinery FASEB J, February 1, 2009; 23(2): 451 - 463. [Abstract] [Full Text] [PDF]