PRA1 promotes the intracellular trafficking and NF-kappaB signaling of EBV latent membrane protein 1.
Latent membrane protein 1 (LMP1), which is an Epstein-Barr virus (EBV)-encoded oncoprotein, induces nuclear factor-kappa B (NF-kappaB) signaling by mimicking the tumor necrosis factor receptor (TNFR). LMP1 signals primarily from intracellular compartments in a ligand-independent manner. Here, we identify a new LMP1-interacting molecule, prenylated Rab acceptor 1 (PRA1), which interacts with LMP1 for the first time through LMP1's transmembrane domain, and show that PRA1 is involved in intracellular LMP1 trafficking and LMP1-induced NF-kappaB activity. Immunofluorescence and biochemical analyses revealed that LMP1 physically interacted with PRA1 at the Golgi apparatus, and the colocalization of LMP1 and PRA1 to the Golgi was sensitive to nocodazole and brefeldin A. Coexpression of a PRA1 export mutant or knockdown of PRA1 led to redistribution of LMP1 and its associated signaling molecules to the endoplasmic reticulum and subsequent impairment of LMP1-induced NF-kappaB activation, but had no effect on CD40- and TNFR1-mediated signaling or the functional integrity of the Golgi apparatus. These novel findings provide important new insights into LMP1, and identify an unexpected new role for PRA1 in cellular signaling.
Liu
Hao-Ping
HP
Institute of Microbiology and Immunology, National Yang Ming University, Shih-Pai, Taipei, Taiwan, Republic of China.
Wu
Chih-Ching
CC
Chang
Yu-Sun
YS
D000818:Animals; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000378:metabolism; D031541:Fluorescence Resonance Energy Transfer; D019204:GTP-Binding Proteins / Q000235:genetics / Q000502:physiology*; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D009154:Mutation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D021381:Protein Transport; D015398:Signal Transduction; D047990:TNF Receptor-Associated Factor 1 / Q000378:metabolism; D048008:TNF Receptor-Associated Factor 3 / Q000378:metabolism; D020798:Two-Hybrid System Techniques; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000502:physiology*; D014763:Viral Matrix Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000097782:NF-kappaB-Inducing Kinase
D019204:GTP-Binding Proteins; D008565:Membrane Proteins; D017346:Protein Serine-Threonine Kinases; D047990:TNF Receptor-Associated Factor 1; D048008:TNF Receptor-Associated Factor 3; D033921:Vesicular Transport Proteins; D014763:Viral Matrix Proteins; D000097782:NF-kappaB-Inducing Kinase; C037662:EBV-associated membrane antigen, Epstein-Barr virus; C108941:RABAC1 protein, human