Dysregulation of INF2-mediated mitochondrial fission in SPOP-mutated prostate cancer
Authors: Jie Wang
Xiaofeng Jin
Yan Tang
Jie Zhu
Haojie Huang
Yao Li
Long Yu
Pingzhao Zhang
Lisha Tang
Chenji Wang
Kun Gao
Longfang Yao
Jian Ma
Jiantao Xiao
Enceng Zhang
Bin Zhang
Shancheng Ren
Shi-Min Zhao
Journal: PLoS Genetics (2017)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: Next-generation sequencing; exome; genome; prostate cancers; genetic alterations
Affiliations: State Key Lab of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, P.R. China., Shanghai Institute of Planned Parenthood Research Hospital, WHO Collaborating Center for Research in Human Reproduction, Shanghai, P.R. China., Fudan University Cancer Institute, Shanghai Cancer Center, Shanghai, P.R. China., Department of Urology, Shanghai First People's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China., Department of hepato-biliary-pancreatic Surgery, Ningbo Medical Center of LiHuiLi Hospital, Ningbo, P.R. China., Department of Urology, Shanghai Changhai Hospital, Second Military Medical University, Shanghai, P.R. China., Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, Minnesota, United States of America.

Abstract:  Next-generation sequencing of the exome and genome of prostate cancers has identified numerous genetic alternations. SPOP (Speckle-type POZ Protein) was one of the most frequently mutated genes in primary prostate cancer, suggesting SPOP is a potential driver of prostate cancer development and progression. However, how SPOP mutations contribute to prostate cancer pathogenesis remains poorly understood. SPOP acts as an adaptor protein of the CUL3-RBX1 E3 ubiquitin ligase complex that generally recruits substrates for ubiquitination and subsequent degradation. ER-localized isoform of the formin protein inverted formin 2 (INF2) mediates actin polymerization at ER-mitochondria intersections and facilitates DRP1 recruitment to mitochondria, which is a critical step in mitochondrial fission. Here, we revealed that SPOP recognizes a Ser/Thr (S/T)-rich motif in the C-terminal region of INF2 and triggers atypical polyubiquitination of INF2. These ubiquitination modifications do not lead to INF2 instability, but rather reduces INF2 localization in ER and mitochondrially associated DRP1 puncta formation, therefore abrogates its ability to facilitate mitochondrial fission. INF2 mutant escaping from SPOP-mediated ubiquitination is more potent in prompting mitochondrial fission. Moreover, prostate cancer-associated SPOP mutants increase INF2 localization in ER and promote mitochondrial fission, probably through a dominant-negative effect to inhibit endogenous SPOP. Moreover, INF2 is important for SPOP inactivation-induced prostate cancer cell migration and invasion. These findings reveal novel molecular events underlying the regulation of INF2 function and localization, and provided insights in understanding the relationship between SPOP mutations and dysregulation of mitochondrial dynamics in prostate cancer. 

Retracted: No

PubPeer comments:
 Figure 8 has multiple image duplications. Seems inconsistent with the different treatments of the cells, and the fact that the Percent cell invasion recorded differs. ![file] , 
 #1 Thank you so much for your interests about this study. We are so sorry for this careless errors. This assay were repeated for 3 times, and we took 3-6 pictures from different visions. Unfortunately, we misused several pitures when we published this manuscript. The attach file is the raw figure (one of the all three repeats) of migration and invasion in this assay. The figures labeled with red lines are now used for the correction for Figure 8H and 8I. Finally, we really appreciated your kindly and good comments on this manuscript and we will also contact the journal shortly for a correction for this figure.![file] , 
 I m not sure what raw figure means. The figure you submitted here also includes duplications. ![file] , 
 #3 Dear Coronilla Vaginalis, we are sorry for the delay of reply. Due to the pandemic and the lock of school, We have spent lots of time to find the original data of transwell. Here we show the one of tree repeats. The authors declare that these corrections do not change the results or conclusions of this paper. We are sorry for the mistakes and Thanks again for your interest. , 
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