Secretion of the adipocyte-specific secretory protein adiponectin critically depends on thiol-mediated protein retention

Zhao V. Wang, Todd D. Schraw, Ja Young Kim, Tayeba Khan, Michael W. Rajala, Antonia Follenzi, Philipp E. Scherer

Research output: Contribution to journalArticle

222 Citations (Scopus)

Abstract

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-Lα, 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.

Original languageEnglish (US)
Pages (from-to)3716-3731
Number of pages16
JournalMolecular and Cellular Biology
Volume27
Issue number10
DOIs
StatePublished - May 2007

Fingerprint

Adiponectin
Sulfhydryl Compounds
Adipocytes
Proteins
Secretory Pathway
PPAR gamma
Biosynthetic Pathways
Reducing Agents
Cysteine
Up-Regulation

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

Secretion of the adipocyte-specific secretory protein adiponectin critically depends on thiol-mediated protein retention. / Wang, Zhao V.; Schraw, Todd D.; Kim, Ja Young; Khan, Tayeba; Rajala, Michael W.; Follenzi, Antonia; Scherer, Philipp E.

In: Molecular and Cellular Biology, Vol. 27, No. 10, 05.2007, p. 3716-3731.

Research output: Contribution to journalArticle

Wang, Zhao V. ; Schraw, Todd D. ; Kim, Ja Young ; Khan, Tayeba ; Rajala, Michael W. ; Follenzi, Antonia ; Scherer, Philipp E. / Secretion of the adipocyte-specific secretory protein adiponectin critically depends on thiol-mediated protein retention. In: Molecular and Cellular Biology. 2007 ; Vol. 27, No. 10. pp. 3716-3731.
@article{3f05d2e734bc416e866c36ad618f23f6,
title = "Secretion of the adipocyte-specific secretory protein adiponectin critically depends on thiol-mediated protein retention",
abstract = "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-Lα, 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.",
author = "Wang, {Zhao V.} and Schraw, {Todd D.} and Kim, {Ja Young} and Tayeba Khan and Rajala, {Michael W.} and Antonia Follenzi and Scherer, {Philipp E.}",
year = "2007",
month = "5",
doi = "10.1128/MCB.00931-06",
language = "English (US)",
volume = "27",
pages = "3716--3731",
journal = "Molecular and Cellular Biology",
issn = "0270-7306",
publisher = "American Society for Microbiology",
number = "10",

}

TY - JOUR

T1 - Secretion of the adipocyte-specific secretory protein adiponectin critically depends on thiol-mediated protein retention

AU - Wang, Zhao V.

AU - Schraw, Todd D.

AU - Kim, Ja Young

AU - Khan, Tayeba

AU - Rajala, Michael W.

AU - Follenzi, Antonia

AU - Scherer, Philipp E.

PY - 2007/5

Y1 - 2007/5

N2 - 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-Lα, 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.

AB - 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-Lα, 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.

UR - http://www.scopus.com/inward/record.url?scp=34248197560&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34248197560&partnerID=8YFLogxK

U2 - 10.1128/MCB.00931-06

DO - 10.1128/MCB.00931-06

M3 - Article

VL - 27

SP - 3716

EP - 3731

JO - Molecular and Cellular Biology

JF - Molecular and Cellular Biology

SN - 0270-7306

IS - 10

ER -