A Chaperone-Like Role for EBI3 in Collaboration With Calnexin Under Inflammatory Conditions

Abstract

The interleukin-6 (IL-6)/IL-12 family of cytokines plays critical roles in the induction and regulation of innate and adaptive immune responses. Among the various cytokines, only this family has the unique characteristic of being composed of two distinct subunits, α- and β-subunits, which form a heterodimer with subunits that occur in other cytokines as well. Recently, we found a novel intracellular role for one of the α-subunits, Epstein-Barr virus-induced gene 3 (EBI3), in promoting the proper folding of target proteins and augmenting its expression at the protein level by binding to its target protein and a well-characterized lectin chaperone, calnexin, presumably through enhancing chaperone activity. Because calnexin is ubiquitously and constitutively expressed but EBI3 expression is inducible, these results could open an avenue to establish a new paradigm in which EBI3 plays an important role in further increasing the expression of target molecules at the protein level in collaboration with calnexin under inflammatory conditions. This theory well accounts for the heterodimer formation of EBI3 with p28, and probably with p35 and p19 to produce IL-27, IL-35, and IL-39, respectively. In line with this concept, another β-subunit, p40, plays a critical role in the assembly-induced proper folding of p35 and p19 to produce IL-12 and IL-23, respectively. Thus, chaperone-like activities in proper folding and maturation, which allow the secretion of biologically active heterodimeric cytokines, have recently been highlighted. This review summarizes the current understanding of chaperone-like activities of EBI3 to form heterodimers and other associations together with their possible biological implications.

Keywords: EBI3; calnexin; chaperone; heterodimer; tumor growth.

Figure 1

Expanding diversity of the IL-6/IL-12 heterodimeric cytokines and their related heterodimeric molecules. Analogous to the complex of IL-6 and soluble IL-6Rα (IL-6/sIL-6Rα), which induces IL-6 trans-signaling in gp130-expressing cells, various heterodimeric cytokines have been reported and their number is still increasing. CLC, cardiotrophin-like cytokine.

Figure 2

EBI3 plays an important role in promoting the formation of proper protein folding in collaboration with calnexin under inflammatory conditions. Calnexin plays a critical role in assisting a quality control ensuring proper folding of most if not all glycoproteins including MHC class I molecules destined for the plasma membrane or secretion by binding to partially folded or misfolded proteins. p62 is a multi-domain and multi-functional adaptor protein, representing not only a selective cargo receptor for autophagy thus inhibiting inflammasome activation and inflammation, but also a central signaling hub, linking several important pro- and anti-inflammatory pathways including Nrf2, mTOR, NF-κB, and so on. Because calnexin expression is constitutive but EBI3 expression is inducible through activation of TLRs and T-cell receptors, calnexin plays a critical role in the formation of proper protein folding under both steady-state conditions and inflammatory conditions, but under inflammatory conditions, EBI3 plays an additional role to further augment it.