Mutual Stabilization between TRIM9 Short Isoform and MKK6 Potentiates p38 Signaling to Synergistically Suppress Glioblastoma Progression

Kunpeng Liu; Chuanxia Zhang; Bowen Li; Weihong Xie; Jindong Zhang; Xichen Nie; Peng Tan; Limin Zheng; Song Wu; Yunfei Qin; Jun Cui; Feng Zhi

doi:10.1016/j.celrep.2018.03.096

Mutual Stabilization between TRIM9 Short Isoform and MKK6 Potentiates p38 Signaling to Synergistically Suppress Glioblastoma Progression

Cell Rep. 2018 Apr 17;23(3):838-851. doi: 10.1016/j.celrep.2018.03.096.

Authors

Kunpeng Liu¹, Chuanxia Zhang¹, Bowen Li², Weihong Xie¹, Jindong Zhang¹, Xichen Nie¹, Peng Tan³, Limin Zheng¹, Song Wu⁴, Yunfei Qin⁵, Jun Cui⁶, Feng Zhi⁷

Affiliations

¹ Key Laboratory of Gene Engineering of the Ministry of Education, School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong 510006, China.
² Department of Neurosurgery, The First People's Hospital of Changzhou, Changzhou, Jiangsu 213000, China; Modern Medical Research Center, Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213000, China.
³ Institute of Biosciences and Technology, Texas A&M University, Health Science Center, Houston, TX 77030, USA.
⁴ Department of Urology Institute of Shenzhen University, Shenzhen Luohu People's Hospital, Shenzhen 518000, China. Electronic address: wusong@szu.edu.cn.
⁵ Key Laboratory of Gene Engineering of the Ministry of Education, School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong 510006, China; Guangdong Provincial Key Laboratory of Liver Disease, Cell-Gene Therapy Translational Medicine Research Center, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510630, China. Electronic address: qinyunfei@163.com.
⁶ Key Laboratory of Gene Engineering of the Ministry of Education, School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong 510006, China; Department of Urology Institute of Shenzhen University, Shenzhen Luohu People's Hospital, Shenzhen 518000, China. Electronic address: cuij5@mail.sysu.edu.cn.
⁷ Department of Neurosurgery, The First People's Hospital of Changzhou, Changzhou, Jiangsu 213000, China; Modern Medical Research Center, Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213000, China. Electronic address: danielzhif@suda.edu.cn.

PMID: 29669288
DOI: 10.1016/j.celrep.2018.03.096

Abstract

p38 signaling is broadly involved in controlling inflammation and stress-induced cell death; however, the mechanisms controlling its activity have seldom been studied. Here, we report that TRIM9 short isoform (TRIM9s) potentiates p38 signaling by stabilizing MKK6. Mechanistic studies revealed that TRIM9s promotes the K63-linked ubiquitination of MKK6 at Lys82, thus inhibiting the degradative K48-linked ubiquitination of MKK6 at the same lysine. MKK6 could also stabilize TRIM9s by promoting the phosphorylation of TRIM9s at Ser76/80 via p38, thereby blocking the ubiquitin-proteasome pathway. Further functional analyses showed that p38 signaling plays a critical role in suppressing glioblastoma progression. Co-reduction of MKK6 and TRIM9s is significantly associated with overall poor survival of glioblastoma patients. We identify a positive feedback loop in p38 signaling generated by MKK6-TRIM9s, which suppresses glioblastoma progression, and we provide insights into the mechanisms by which TRIM9s and MKK6 potentiate p38 signaling through mutual stabilization.

MeSH terms

Animals
Cell Line, Tumor
Glioblastoma / drug therapy
Glioblastoma / mortality
Glioblastoma / pathology*
Humans
MAP Kinase Kinase 6 / deficiency
MAP Kinase Kinase 6 / genetics
MAP Kinase Kinase 6 / metabolism*
Mice
Mice, Inbred BALB C
Mice, Nude
Nerve Tissue Proteins / antagonists & inhibitors
Nerve Tissue Proteins / genetics
Nerve Tissue Proteins / metabolism*
Phosphorylation
Protein Isoforms / antagonists & inhibitors
Protein Isoforms / genetics
Protein Isoforms / metabolism
RNA Interference
RNA, Small Interfering / metabolism
RNA, Small Interfering / therapeutic use
Signal Transduction*
Survival Rate
Tripartite Motif Proteins / antagonists & inhibitors
Tripartite Motif Proteins / genetics
Tripartite Motif Proteins / metabolism*
Ubiquitin / metabolism
Ubiquitin-Protein Ligases / antagonists & inhibitors
Ubiquitin-Protein Ligases / genetics
Ubiquitin-Protein Ligases / metabolism*
Ubiquitination
p38 Mitogen-Activated Protein Kinases / metabolism

Substances

Nerve Tissue Proteins
Protein Isoforms
RNA, Small Interfering
Tripartite Motif Proteins
Ubiquitin
TRIM9 protein, human
Ubiquitin-Protein Ligases
p38 Mitogen-Activated Protein Kinases
MAP Kinase Kinase 6
MAP2K6 protein, human