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

Kun Zhang; Yilu Lu; Ping Yang; Chao Li; Huaqin Sun; Dachang Tao; Yunqiang Liu; Sizhong Zhang; Yongxin Ma

doi:10.1371/journal.pone.0041973

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

PLoS One. 2012;7(7):e41973. doi: 10.1371/journal.pone.0041973. Epub 2012 Jul 27.

Authors

Kun Zhang¹, Yilu Lu, Ping Yang, Chao Li, Huaqin Sun, Dachang Tao, Yunqiang Liu, Sizhong Zhang, Yongxin Ma

Affiliation

¹ Department of Medical Genetics, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Apoptosis / drug effects
Argonaute Proteins / metabolism*
HEK293 Cells
HSP90 Heat-Shock Proteins / metabolism*
Humans
Phosphorylation / drug effects
Protein Binding
Protein Serine-Threonine Kinases / metabolism*
Proteolysis* / drug effects
Receptor, Transforming Growth Factor-beta Type I
Receptor, Transforming Growth Factor-beta Type II
Receptors, Transforming Growth Factor beta / metabolism*
Signal Transduction* / drug effects
Smad Proteins / metabolism
Transforming Growth Factor beta / metabolism*
Transforming Growth Factor beta / pharmacology
Ubiquitin-Protein Ligases / metabolism

Substances

Argonaute Proteins
HSP90 Heat-Shock Proteins
PIWIL2 protein, human
Receptors, Transforming Growth Factor beta
Smad Proteins
Transforming Growth Factor beta
SMURF2 protein, human
Ubiquitin-Protein Ligases
Protein Serine-Threonine Kinases
Receptor, Transforming Growth Factor-beta Type I
Receptor, Transforming Growth Factor-beta Type II

Grants and funding

This work is supported by National Basic Research Program of China (973 Program, grant no. 2012CB947600), National Natural Science Foundation of China (grant no. 90919006 and 31070676), Trans-Century Training Programme Foundation for the Talents by the Ministry of Education of China (grant no. NCET-07-0580) and Spring Sunshine Programme by the Ministry of Education of China (grant no. Z2009-1-61003). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.