A disulfide-bond A oxidoreductase-like protein (DsbA-L) regulates adiponectin multimerization.
Impairments in adiponectin multimerization lead to defects in adiponectin secretion and function and are associated with diabetes, yet the underlying mechanisms remain largely unknown. We have identified an adiponectin-interacting protein, previously named GST-kappa, by yeast 2-hybrid screening. The adiponectin-interacting protein contains 2 thioredoxin domains and has very little sequence similarity to other GST isoforms. However, this protein shares high sequence and secondary structure homology to bacterial disulfide-bond A oxidoreductase (DsbA) and is thus renamed DsbA-like protein (DsbA-L). DsbA-L is highly expressed in adipose tissue, and its expression level is negatively correlated with obesity in mice and humans. DsbA-L expression in 3T3-L1 adipocytes is stimulated by the insulin sensitizer rosiglitazone and inhibited by the inflammatory cytokine TNFalpha. Overexpression of DsbA-L promoted adiponectin multimerization while suppressing DsbA-L expression by RNAi markedly and selectively reduced adiponectin levels and secretion in 3T3-L1 adipocytes. Our results identify DsbA-L as a key regulator for adiponectin biosynthesis and uncover a potential new target for developing therapeutic drugs for the treatment of insulin resistance and its associated metabolic disorders.
Liu
Meilian
M
Department of Pharmacology, University of Texas Health Science Center, San Antonio, TX 78229, USA.
Zhou
Lijun
L
Xu
Aimin
A
Lam
Karen S L
KS
Wetzel
Michael D
MD
Xiang
Ruihua
R
Zhang
Jingjing
J
Xin
Xiaoban
X
Dong
Lily Q
LQ
Liu
Feng
F
D041721:3T3-L1 Cells; D052242:Adiponectin / Q000737:chemistry* / Q000378:metabolism; D000328:Adult; D000818:Animals; D055162:Biocatalysis; D001704:Biopolymers / Q000737:chemistry*; D016022:Case-Control Studies; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D005982:Glutathione Transferase / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D018832:Molecular Chaperones / Q000378:metabolism / Q000502:physiology*; D009765:Obesity / Q000378:metabolism; D017510:Protein Folding; D011499:Protein Processing, Post-Translational; D034622:RNA Interference; D014158:Transcription, Genetic; D020798:Two-Hybrid System Techniques
D052242:Adiponectin; D001704:Biopolymers; D018832:Molecular Chaperones; C487896:GSTK1 protein, human; D005982:Glutathione Transferase