SVIP induces localization of p97/VCP to the plasma and lysosomal membranes and regulates autophagy

• Published in: PloS one Vol. 6; no. 8; p. e24478
• Main Authors: Wang, Yang, Ballar, Petek, Zhong, Yongwang, Zhang, Xuebao, Liu, Chao, Zhang, Ying-Jiu, Monteiro, Mervyn J, Li, Jun, Fang, Shengyun
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 31.08.2011; Public Library of Science (PLoS)
• Subjects: Adaptor Proteins, Signal Transducing - metabolism; Adenosine Triphosphatases - metabolism; Animals; Apoptosis; Autophagy; Biology; Biomedical engineering; Brain - cytology; Brain - metabolism; Brain research; Carrier Proteins - metabolism; Cell Cycle Proteins - metabolism; Cell death; Cell growth; Cell Line; Cell Membrane - metabolism; Endoplasmic reticulum; Engineering; Enzymes; Gene Knockdown Techniques; Green Fluorescent Proteins; Homeostasis; Humans; Intracellular Membranes - metabolism; Laboratories; Localization; Lysosomal Membrane Proteins - metabolism; Lysosomes - metabolism; Membrane Proteins; Membranes; Mice; Microtubule-Associated Proteins - metabolism; Motor Neurons - cytology; Motor Neurons - metabolism; mRNA; Nuclear Proteins - metabolism; p62 Protein; Phagocytosis; Phagosomes; Phagosomes - metabolism; Phosphate-Binding Proteins; Protein Transport; Proteins; Recombinant Fusion Proteins - metabolism; Rodents; Sequestosome-1 Protein; Spinal cord; Spinal Cord - cytology; Spinal Cord - metabolism; Ubiquitination; Vacuoles; Vacuoles - metabolism; Valosin Containing Protein; United States > US; Maryland; Tennessee; China; Nashville Tennessee; Baltimore Maryland
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0024478

The small p97/VCP-interacting protein (SVIP) functions as an inhibitor of the endoplasmic reticulum (ER)-associated degradation (ERAD) pathway. Here we show that overexpression of SVIP in HeLa cells leads to localization of p97/VCP at the plasma membrane, intracellular foci and juxtanuclear vacuoles. The p97/VCP-positive vacuolar structures colocalized or associated with LC3 and lamp1, suggesting that SVIP may regulate autophagy. In support of this possibility, knockdown of SVIP diminished, whereas overexpression of SVIP enhanced LC3 lipidation. Surprisingly, knockdown of SVIP reduced the levels of p62 protein at least partially through downregulation of its mRNA, which was accompanied by a decrease in starvation-induced formation of p62 bodies. Overexpression of SVIP, on the other hand, increased the levels of p62 protein and enhanced starvation-activated autophagy as well as promoted sequestration of polyubiquitinated proteins and p62 in autophagosomes. These results suggest that SVIP plays a regulatory role in p97 subcellular localization and is a novel regulator of autophagy.