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Molecular and Cellular Biology, November 2008, p. 6796-6818, Vol. 28, No. 22
0270-7306/08/$08.00+0     doi:10.1128/MCB.00800-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Disrupting Vesicular Trafficking at the Endosome Attenuates Transcriptional Activation by Gcn4{triangledown}

Fan Zhang,1,{dagger} Naseem A. Gaur,1,{dagger} Jiri Hasek,2 Soon-ja Kim,1 Hongfang Qiu,1 Mark J. Swanson,1 and Alan G. Hinnebusch1*

Laboratory of Gene Regulation and Development, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892,1 Institute of Microbiology, Academy of Sciences of the Czech Republic, Prague, Czech Republic2

Received 16 May 2008/ Returned for modification 12 June 2008/ Accepted 2 September 2008

The late endosome (MVB) plays a key role in coordinating vesicular transport of proteins between the Golgi complex, vacuole/lysosome, and plasma membrane. We found that deleting multiple genes involved in vesicle fusion at the MVB (class C/D vps mutations) impairs transcriptional activation by Gcn4, a global regulator of amino acid biosynthetic genes, by decreasing the ability of chromatin-bound Gcn4 to stimulate preinitiation complex assembly at the promoter. The functions of hybrid activators with Gal4 or VP16 activation domains are diminished in class D mutants as well, suggesting a broader defect in activation. Class E vps mutations, which impair protein sorting at the MVB, also decrease activation by Gcn4, provided they elicit rapid proteolysis of MVB cargo proteins in the aberrant late endosome. By contrast, specifically impairing endocytic trafficking from the plasma membrane, or vesicular transport to the vacuole, has a smaller effect on Gcn4 function. Thus, it appears that decreasing cargo proteins in the MVB through impaired delivery or enhanced degradation, and not merely the failure to transport cargo properly to the vacuole or downregulate plasma membrane proteins by endocytosis, is required to attenuate substantially transcriptional activation by Gcn4.

* Corresponding author. Mailing address: NIH, Building 6A/Room B1A-13, Bethesda, MD 20892. Phone: (301) 496-4480. Fax: (301) 496-6828. E-mail: ahinnebusch{at}nih.gov

{triangledown} Published ahead of print on 15 September 2008.

{dagger} F.Z. and N.A.G. contributed equally.

Molecular and Cellular Biology, November 2008, p. 6796-6818, Vol. 28, No. 22
0270-7306/08/$08.00+0     doi:10.1128/MCB.00800-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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