The Golgi-associated protein p115 mediates the secretion of macrophage migration inhibitory factor.
Macrophage migration inhibitory factor (MIF) is a leaderless protein that is secreted from cells by a specialized, nonclassical export pathway. The release of MIF nevertheless is regulated and its production in response to different inflammatory, mitogenic, and hormonal stimuli plays an important role in diverse physiologic and pathologic processes. We report herein the identification of the Golgi complex-associated protein p115 as an intracellular binding partner for MIF. MIF interacts with p115 in the cytoplasm and the stimulated secretion of MIF results in the accumulation of both proteins in supernatants, which is consistent with MIF release from cells in conjunction with p115. The depletion of p115 from monocytes/macrophages decreases the release of MIF but not other cytokines following inflammatory stimulation or intracellular bacterial infection. Notably, the small molecule MIF inhibitor 4-iodo-6-phenylpyrimidine inhibits MIF secretion by targeting the interaction between MIF and p115. These data reveal p115 to be a critical intermediary component in the regulated secretion of MIF from monocytes/macrophages.
Merk
Melanie
M
Yale University School of Medicine, New Haven, CT 06520, USA.
Baugh
John
J
Zierow
Swen
S
Leng
Lin
L
Pal
Utpal
U
Lee
Seung Joon
SJ
Ebert
Antje D
AD
Mizue
Yuka
Y
Trent
John O
JO
Mitchell
Robert
R
Nickel
Walter
W
Kavathas
Paula B
PB
Bernhagen
Jürgen
J
Bucala
Richard
R
D002460:Cell Line; D003593:Cytoplasm / Q000378:metabolism; D000077614:Golgi Matrix Proteins; D006801:Humans; D008263:Macrophage Migration-Inhibitory Factors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D009000:Monocytes / Q000378:metabolism; D011485:Protein Binding; D011743:Pyrimidines / Q000494:pharmacology; D033921:Vesicular Transport Proteins / Q000378:metabolism*
C532251:4-iodo-6-phenylpyrimidine; D000077614:Golgi Matrix Proteins; D008263:Macrophage Migration-Inhibitory Factors; D011743:Pyrimidines; D033921:Vesicular Transport Proteins; C091580:vesicular transport factor p115