Regulation of inducible nitric oxide synthase by aggresome formation

doi:10.1073/pnas.0500485102

Regulation of inducible nitric oxide synthase by aggresome formation

Departments of ^*Medicine, ^†Pediatrics, and ^‡Molecular Cell Biology, Baylor College of Medicine, Houston, TX 77030

Edited by Solomon H. Snyder, Johns Hopkins University School of Medicine, Baltimore, MD, and approved February 15, 2005 (received for review January 19, 2005)

Abstract

Misfolding and aggregation of proteins play an important part in the pathogenesis of several genetic and degenerative diseases. Recent evidence suggests that cells have evolved a pathway that involves sequestration of aggregated proteins into specialized “holding stations” called aggresomes. Here we show that cells regulate inducible NO synthase (iNOS), an important host defense protein, through aggresome formation. iNOS aggresome formation depends on a functional dynein motor and the integrity of the microtubules. The iNOS aggresome represents a “physiologic aggresome” and thus defines a new paradigm for cellular regulation of protein processing. This study indicates that aggresome formation in response to misfolded proteins may merely represent an acceleration of an established physiologic regulatory process for specific proteins whose regulation by aggresome formation is deemed necessary by the cell.

Footnotes

↵ ¶ To whom correspondence should be addressed. E-mail: teissa{at}bcm.tmc.edu.
↵ § Present address: Pacific Northwest National Laboratory, Richland, WA 99352.
Author contributions: K.E.K., A.R.B., R.H.M., D.L.S., and N.T.E. designed research; K.E.K., A.R.B., and D.L.S. performed research; K.E.K., A.R.B., R.H.M., and N.T.E. analyzed data; and K.E.K., A.R.B., and N.T.E. wrote the paper.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations: iNOS, inducible NO synthase; HEK, human embryonic kidney; DIC, Normaski differential interference contrast; MTOC, microtubule-organizing center.