MAPK scaffolding by BIT1 in the Golgi complex modulates stress resistance.
The endoplasmic reticulum (ER) is an essential organelle whose major functions are to ensure proper secretory protein folding and trafficking. These mechanisms involve the activation of specific ER-resident molecular machines, which might be regulated by their membranous environments. Based on this observation, we aimed to characterize the proteome of ER-membrane microdomains to identify new components of the ER that have a role in secretory pathway-associated functions. Using this approach with dog pancreatic rough microsomes, we found that mitochondrial Bcl-2 inhibitor of transcription (BIT1) localized in the early secretory pathway and accumulated in the Golgi complex. Using both a chimeric protein of the luminal and transmembrane domains of ER-resident TRAPalpha and the cytosolic domain of BIT1, and silencing of BIT1 expression, we perturbed endogenous BIT1 oligomerization and localization to the Golgi. This led to enhanced ERK signaling from the Golgi complex, which resulted in improved stress resistance. This work provides the first evidence for the existence of ER microdomains that are involved in the regulation of BIT1 structure and trafficking, and identifies BIT1 as a negative regulator of the ERK-MAPK signaling pathway in the Golgi.
Yi
Ping
P
Avenir, INSERM U889, Bordeaux, France.
Nguyên
Duc Thang
DT
Higa-Nishiyama
Arisa
A
Auguste
Patrick
P
Bouchecareilh
Marion
M
Dominguez
Michel
M
Bielmann
Regula
R
Palcy
Sandrine
S
Liu
Jian Feng
JF
Chevet
Eric
E
D000135:Acid Phosphatase / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002265:Carboxylic Ester Hydrolases / Q000235:genetics / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D004285:Dogs; D018870:Endoplasmic Reticulum, Rough / Q000378:metabolism; D005818:Genetic Engineering; D006056:Golgi Apparatus / Q000378:metabolism*; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000235:genetics; D008861:Microsomes / Q000378:metabolism / Q000648:ultrastructure; D008928:Mitochondria / Q000378:metabolism; D046912:Multiprotein Complexes / Q000378:metabolism*; D010179:Pancreas / Q000648:ultrastructure; D021381:Protein Transport / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism*; D013312:Stress, Physiological; D000071681:Tartrate-Resistant Acid Phosphatase
D007527:Isoenzymes; D046912:Multiprotein Complexes; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; D002265:Carboxylic Ester Hydrolases; C019674:aminoacyl-tRNA hydrolase; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase