Regulated secretion of macrophage migration inhibitory factor is mediated by a non‐classical pathway involving an ABC transporter

Abstract

The cytokine macrophage migration inhibitory factor (MIF) is inducibly secreted by immune cells and certain other cell types to critically participate in the regulation of the host immune response. However, MIF does not contain a N-terminal signal sequence and the mechanism of MIF secretion is unknown. Here we show in a model of endotoxin-stimulated THP-1 monocytes that MIF does not enter the endoplasmatic reticulum and that MIF secretion is not inhibited by monensin or brefeldin A, demonstrating that MIF secretion occurs via a non-classical export route. Glyburide and probenicide but not other typical inhibitors of non-classical protein export strongly block MIF secretion, indicating that the export pathway of MIF involves an ABCA1 transporter. ß

Macrophage migration inhibitory factor (MIF) promotes cell survival by activation of the Akt pathway and role for CSN5/JAB1 in the control of autocrine MIF activity

“…JAB1 is part of the CSN, which is located in the nucleus and cytoplasm, where it can interact with MIF (Kleemann et al, 2000;Chamovitz and Segal, 2001;Bech-Otschir et al, 2002). MIF is secreted from immune cells and fibroblasts by a nonconventional export pathway bypassing the ER/Golgi apparatus (Flieger et al, 2003;Nickel, 2003). Upon protein synthesis, MIF is 'stored' in the cytosol before translocation into a secretion competent, yet unidentified, vesicular compartment (Bernhagen et al, 1993;Flieger et al, 2003).…”

“…MIF is secreted from immune cells and fibroblasts by a nonconventional export pathway bypassing the ER/Golgi apparatus (Flieger et al, 2003;Nickel, 2003). Upon protein synthesis, MIF is 'stored' in the cytosol before translocation into a secretion competent, yet unidentified, vesicular compartment (Bernhagen et al, 1993;Flieger et al, 2003). This latter process is dependent on an ABCA1 transporter (Flieger et al, 2003), and our current study demonstrates that JAB1 can retain MIF in the cytosol.…”

“…In fact, MIF is prestored intracellularly and released upon stimulation, but also continuously by cycling tumor cells (Bernhagen et al, 1993;Mitchell and Bucala, 2000;Flieger et al, 2003). Activation of sustained ERK signaling is mediated by autocrine MIF action (Mitchell et al, 1999).…”

“…Role for JAB1 in MIF secretion and autocrine MIFmediated Akt signaling Intracellular MIF is a store for MIF secretion via the unconventional export pathway (Bernhagen et al, 1993;Flieger et al, 2003) and interacts with JAB1 (Kleemann et al, 2000). We investigated the possibility that JAB1 could act as a regulator of MIF secretion to control Akt signaling by interference with the autocrine MIF loop.…”

MIF from mussel: Coding sequence, phylogeny, polymorphism, 3D model and regulation of expression

“…One of them is related to the absence of signal peptide reported in murine, human and fish MIF sequences, as we observed in M. galloprovincialis. Thus, evidence suggested that MIF does not travel to the endoplasmic reticulum, instead it is secreted via a non-classical export pathway involving an ATP binding cassette transporter (Flieger et al, 2003). MIF is part of the growing list of cytokines, such as interleukin-1 (IL-1) and basic fibroblast growth factor (bFGF), which are released from cells by non-classical pathways.…”