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Molecular and Cellular Biology, May 2007, p. 3716-3731, Vol. 27, No. 10
0270-7306/07/$08.00+0     doi:10.1128/MCB.00931-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Secretion of the Adipocyte-Specific Secretory Protein Adiponectin Critically Depends on Thiol-Mediated Protein Retention{triangledown} ,{dagger}

Zhao V. Wang,1 Todd D. Schraw,1,{ddagger} Ja-Young Kim,1 Tayeba Khan,1 Michael W. Rajala,1,§ Antonia Follenzi,2,3 and Philipp E. Scherer1,4,5*

Departments of Cell Biology,1 Pathology,2 Medicine,4 Diabetes Research and Training Center,5 Marion Bessin Liver Research Center, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 104613

Received 26 May 2006/ Returned for modification 24 July 2006/ Accepted 26 February 2007

Adiponectin is a secretory protein abundantly secreted from adipocytes. It assembles into a number of different higher-order complexes. Adipocytes maintain tight control over circulating plasma levels, suggesting the existence of a complex, highly regulated biosynthetic pathway. However, the critical mediators of adiponectin maturation within the secretory pathway have not been elucidated. Previously, we found that a significant portion of de novo-synthesized adiponectin is not secreted and retained in adipocytes. Here, we show that there is an abundant pool of properly folded adiponectin in the secretory pathway that is retained through thiol-mediated retention, as judged by the release of adiponectin in response to treatment of adipocytes with reducing agents. Adiponectin is covalently bound to the ER chaperone ERp44. An adiponectin mutant lacking cysteine 39 fails to stably interact with ERp44, demonstrating that this residue is the primary site mediating the covalent interaction. Another ER chaperone, Ero1-L{alpha}, plays a critical role in the release of adiponectin from ERp44. Levels of both of these proteins are highly regulated in adipocytes and are influenced by the metabolic state of the cell. While less critical for the secretion of trimers, these chaperones play a major role in the assembly of higher-order adiponectin complexes. Our data highlight the importance of posttranslational events controlling adiponectin levels and the release of adiponectin from adipocytes. One mechanism for increasing circulating levels of specific adiponectin complexes by peroxisome proliferator-activated receptor gamma agonists may be selective upregulation of rate-limiting chaperones.

* Corresponding author. Present address: Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9077. Phone: (214) 648-8715. Fax: (214) 648-8720. E-mail: philipp.scherer{at}utsouthwestern.edu

{triangledown} Published ahead of print on 12 March 2007.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} Present address: Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9077.

§ Present address: Department of Medicine, University of Michigan, Ann Arbor, MI 48109.

Molecular and Cellular Biology, May 2007, p. 3716-3731, Vol. 27, No. 10
0270-7306/07/$08.00+0     doi:10.1128/MCB.00931-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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