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.

Epstein-Barr virus induced 3 attributes to TLR7-mediated splenomegaly and bicytopenia

“…Since EBI3 has multiple functions in immune regulation, we might need to consider other functions of EBI3. EBI3 binds to IL-12p35 and IL-23p19 and functions as heterodimer cytokines named IL-35 and IL-39, respectively (5). EBI3 also serves as a molecular chaperone in conjunction with calnexin in CD4 + T cells during inflammation (45).…”

“…EBI3 is expressed in a variety of immune cells (1)(2)(3), and its expression is induced by stimulation of Toll-like receptors (TLRs) (4). It binds to IL-27p28 and functions as a heterodimer cytokine named IL-27 (5). IL-27 is a cytokine that functions in both innate and acquired immunity.…”

The potential novel immune-related prognostic factors for acute myeloid leukemia

“…CANX (calnexin), an endoplasmic reticulum (ER) lectin chaperone, participates in the synthesis of HLA class I surface antigen complex, protein folding, cellular energy balance, and autophagy-related process in several ways [24][25][26][27]. Azuma Y et al found that CANX and CRT could be translocated to the cell surface by cellular stresses and chemotherapeutic drugs, such as mitoxantrone.…”

IL-27 expression regulation and its effects on adaptive immunity against viruses

“…In contrast, the human IL-27p28 has only one cysteine residue and therefore lacks a disulfide-bond, instead requiring EBI3 binding for its secretion ( 10 , 13 , 43 – 46 ). The EBI3 subunit acts as chaperone-like protein and this property facilitates the secretion of non-disulfide-linked IL-27, IL-35, and IL-39 ( 45 , 47 ).…”

“…EBI3 is induced under inflammatory conditions and independently secreted, even in the absence of the subunits IL-27p28, IL-35p35 or IL-39p19. This has led to the hypothesis that EBI3 plays additional roles including a chaperone-like and regulatory functions ( 47 , 67 , 70 , 71 , 81 , 82 ).…”