HILI inhibits TGF-β signaling by interacting with Hsp90 and promoting TβR degradation

• Published in: PloS one 2012-07, Vol.7 (7), p.e41973
• Main Authors: Zhang, Kun, Lu, Yilu, Yang, Ping, Li, Chao, Sun, Huaqin, Tao, Dachang, Liu, Yunqiang, Zhang, Sizhong, Ma, Yongxin
• Format: Article
• Language: English
• Subjects: Apoptosis; Apoptosis - drug effects; Argonaute Proteins - metabolism; Biology; Cell cycle; Cell self-renewal; Cyclin-dependent kinases; Degradation; Drosophila; Embryogenesis; Embryonic growth stage; Genes; Genetics; Growth factors; Heat shock proteins; HEK293 Cells; HSP90 Heat-Shock Proteins - metabolism; Hsp90 protein; Human performance; Humans; Insects; Kinases; Laboratories; Pathogenesis; Phosphorylation; Phosphorylation - drug effects; Protein Binding; Protein-Serine-Threonine Kinases - metabolism; Protein-serine/threonine kinase; Proteolysis - drug effects; Receptors; Receptors, Transforming Growth Factor beta - metabolism; Ribonucleic acid; RNA; RNA-mediated interference; Signal transduction; Signal Transduction - drug effects; Signaling; Smad Proteins - metabolism; Smad2 protein; Stem cells; Studies; Threonine; Transforming Growth Factor beta - metabolism; Transforming Growth Factor beta - pharmacology; Transforming growth factor-a; Transforming growth factor-b; Ubiquitin; Ubiquitin-protein ligase; Ubiquitin-Protein Ligases - metabolism; Ubiquitination
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0041973

PIWIL2, called HILI in humans, is a member of the PIWI subfamily. This subfamily has highly conserved PAZ and Piwi domains and is implicated in several critical functions, including embryonic development, stem-cell self-renewal, RNA silencing, and translational control. However, the underlying molecular mechanism remains largely unknown. Transforming growth factor-β (TGF-β) is a secreted multifunctional protein that controls several developmental processes and the pathogenesis of many diseases. TGF-β signaling is activated by phosphorylation of transmembrane serine/threonine kinase receptors, TGF-β type II (TβRII), and type I (TβRI), which are stabilized by Hsp90 via specific interactions with this molecular chaperone. Here, we present evidence that HILI suppresses TGF-β signaling by physically associating with Hsp90 in human embryonic kidney cells (HEK-293). Our research shows that HILI mediates the loss of TGF-β-induced Smad2/3 phosphorylation. We also demonstrate that HILI interacts with Hsp90 to prevent formation of Hsp90-TβR heteromeric complexes, and improves ubiquitination and degradation of TβRs dependent on the ubiquitin E3 ligase Smurf2. This work reveals a critical negative regulation level of TGF-β signaling mediated by HILI (human PIWIL2) by its ability to interact with Hsp90 and promote TβR degradation.