RRC ID 68648
Author Shen M, Siu S, Byrd S, Edelmann KH, Patel N, Ketchem RR, Mehlin C, Arnett HA, Hasegawa H.
Title Diverse functions of reactive cysteines facilitate unique biosynthetic processes of aggregate-prone interleukin-31.
Journal Exp Cell Res
Abstract 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.
Volume 317(7)
Pages 976-93
Published 2011-4-15
DOI 10.1016/j.yexcr.2010.12.012
PII S0014-4827(10)00570-7
PMID 21182835
MeSH Animals Cell Line Cell Proliferation Cysteine / metabolism* Endoplasmic Reticulum / metabolism Golgi Apparatus / metabolism HEK293 Cells Humans Inclusion Bodies / chemistry* Interleukins / biosynthesis* Interleukins / genetics Mice Protein Processing, Post-Translational Signal Transduction / physiology
IF 3.383
Resource
Human and Animal Cells Ba/F3(RCB0805)