Diverse functions of reactive cysteines facilitate unique biosynthetic processes of aggregate-prone interleukin-31.

Authors:
Min Shen
Min Shen
National Center for Advancing Translational Sciences
China
Sophia Siu
Sophia Siu
Wills Eye Institute
United States
Kurt H Edelmann
Kurt H Edelmann
The Scripps Research Institute
United States
Neha Patel
Neha Patel
Department of Otolaryngology
St. Louis | United States
Randal R Ketchem
Randal R Ketchem
National Institute of Standards and Technology
United States
Christopher Mehlin
Christopher Mehlin
University of Washington
United States
Heather A Arnett
Heather A Arnett
One Amgen Center Drive
United States

Exp Cell Res 2011 Apr 21;317(7):976-93. Epub 2010 Dec 21.

Department of Protein Science, Amgen Inc, Seattle, WA 98119, USA.

Interleukin-31 (IL-31) is a member of the four helical-bundle gp130/IL-6 cytokine family. Despite its implicated roles in inflammatory diseases, the biosynthetic processes of IL-31 have been poorly investigated. A detailed understanding of IL-31 biosynthesis and the nature of ligand-receptor interactions can provide insights into effective strategies for the design of therapeutic approaches. By using various heterologous protein expression systems, we demonstrated that murine IL-31 was secreted as inter-molecularly disulfide-bonded covalent aggregates. Covalently aggregated IL-31 appeared while trafficking in the secretory pathway, but was not actively retained in the ER. The aggregate formation was not caused by a dysfunctional ER quality control mechanism or an intrinsic limitation in protein folding capacity. Furthermore, secreted IL-31 aggregates were part of a large complex composed of various pleiotropic secretory factors and immune-stimulators. The extent and the heterogeneous nature of aggregates may imply that IL-31 was erroneously folded, but it was capable of signaling through cognate receptors. Mutagenesis revealed the promiscuity of all five cysteines in inter-molecular disulfide formation with components of the hetero-aggregates, but no cysteine was required for IL-31 secretion itself. Our present study not only illustrated various functions that cysteines perform during IL-31 biosynthesis and secretion, but also highlighted their potential roles in cytokine effector functions.

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http://dx.doi.org/10.1016/j.yexcr.2010.12.012DOI Listing

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April 2011
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