1. MCPIP1 ribonuclease exhibits broad-spectrum antiviral effects through viral RNA binding and degradation
Ren-Jye Lin, Bi-Lan Chang, Wei-Chun Tang, Hsu-Ling Chien, Han-Pang Yu, Yi-Ling Lin, Shyr-Yi Lin Nucleic Acids Res . 2013 Mar 1;41(5):3314-26. doi: 10.1093/nar/gkt019.
Monocyte chemoattractant protein 1-induced protein 1 (MCPIP1), belonging to the MCPIP family with highly conserved CCCH-type zinc finger and Nedd4-BP1, YacP Nuclease domains, has been implicated in negative regulation of the cellular inflammatory responses. In this report, we demonstrate for the first time that this RNA-binding nuclease also targets viral RNA and possesses potent antiviral activities. Overexpression of the human MCPIP1, but not MCPIP2, MCPIP3 or MCPIP4, inhibited Japanese encephalitis virus (JEV) and dengue virus (DEN) replication. The functional analysis of MCPIP1 revealed that the activities of RNase, RNA binding and oligomerization, but not deubiqutinase, are required for its antiviral potential. Furthermore, infection of other positive-sense RNA viruses, such as sindbis virus and encephalomyocarditis virus, and negative-sense RNA virus, such as influenza virus, as well as DNA virus, such as adenovirus, can also be blocked by MCPIP1. Moreover, the endogenous MCPIP1 gene expression was induced by JEV and DEN infection, and knockdown of MCPIP1 expression enhanced the replication of JEV and DEN in human cells. Thus, MCPIP1 can act as a host innate defense via RNase activity for targeting and degrading viral RNA.
2. A selective WDR5 degrader inhibits acute myeloid leukemia in patient-derived mouse models
Yi-Hsuan Tsai, Laura Herring, H Ümit Kaniskan, Rinku Jain, Huen Suk Kim, Gang Greg Wang, Aneel K Aggarwal, Yudao Shen, Weida Gong, Jithesh Kottur, Dongxu Li, Jian Jin, Ling Cai, Kwang-Su Park, Jun Wang, Jing Liu, Joel Parker, Xufen Yu, Kyogo Suzuki Sci Transl Med . 2021 Sep 29;13(613):eabj1578. doi: 10.1126/scitranslmed.abj1578.
Interactions between WD40 repeat domain protein 5 (WDR5) and its various partners such as mixed lineage leukemia (MLL) and c-MYC are essential for sustaining oncogenesis in human cancers. However, inhibitors that block protein-protein interactions (PPIs) between WDR5 and its binding partners exhibit modest cancer cell killing effects and lack in vivo efficacy. Here, we present pharmacological degradation of WDR5 as a promising therapeutic strategy for treating WDR5-dependent tumors and report two high-resolution crystal structures of WDR5-degrader-E3 ligase ternary complexes. We identified an effective WDR5 degrader via structure-based design and demonstrated its in vitro and in vivo antitumor activities. On the basis of the crystal structure of an initial WDR5 degrader in complex with WDR5 and the E3 ligase von Hippel-Lindau (VHL), we designed a WDR5 degrader, MS67, and demonstrated the high cooperativity of MS67 binding to WDR5 and VHL by another ternary complex structure and biophysical characterization. MS67 potently and selectively depleted WDR5 and was more effective than WDR5 PPI inhibitors in suppressing transcription of WDR5-regulated genes, decreasing the chromatin-bound fraction of MLL complex components and c-MYC, and inhibiting the proliferation of cancer cells. In addition, MS67 suppressed malignant growth of MLL-rearranged acute myeloid leukemia patient cells in vitro and in vivo and was well tolerated in vivo. Collectively, our results demonstrate that structure-based design can be an effective strategy to identify highly active degraders and suggest that pharmacological degradation of WDR5 might be a promising treatment for WDR5-dependent cancers.
3. Visceral adiposity index outperforms conventional anthropometric assessments as predictor of diabetes mellitus in elderly Chinese: a population-based study
Ying-Ju Chen, Yu-Chen Chang, Wei-Hsin Huang, Chun-Ho Yun, Ta-Chuan Hung, Kuang-Chun Hu, Chung-Lieh Hung, Jen-Yuan Kuo, Kuo-Tzu Sung, Tung-Ying Chen, Ching-Ping Hsu, Chia-Yuan Liu, Chuan-Chuan Liu, Meng-Ting Tsou, Yang-Che Kuo, Hung-I Yeh Nutr Metab (Lond) . 2021 Sep 25;18(1):87. doi: 10.1186/s12986-021-00608-6.
Background:This study assessed the performance of visceral adiposity index and body shape index in predicting diabetes mellitus (DM) risk and compared their predictive ability to that of body mass index and waist circumference.Methods:Among 8249 consecutive subjects who attended the Nationwide Health Check Up System for Senior Citizens (≥ 65 years) between 2008 and 2018, we examined the associations of several adiposity indices with DM risk and explored gender differences.Results:Among all adiposity indicators, Chinese visceral adiposity index (CVAI) demonstrated the highest discriminatory ability for diabetes mellitus with area under receiver operating characteristic curves (AUC) of 0.65, 0.68, and 0.66 for men, women, and all participants, respectively, and optimal cut-offs set as 126.09 in men and 117.77 in women. Compared with body shape index (ABSI), both CVAI and VAI were strongly associated with baseline DM (adjusted OR: 4.85, 95% CI: 4.05-5.82 and 4.22, 95% CI: 3.53-5.05 for 4th vs 1st quartile groups by CVAI and VAI, P < 0.001), which was more pronounced in older adult women (Pinteraction< 0.05). Over a median of 5.25 years (IQR: 3.07-6.44 years) follow-up, Cox regression models showed higher predictive ability of CVAI and VAI compared to ABSI. Further, both CVAI and VAI independently predicted new-onset DM (adjusted HR: 1.29, 95% CI: 1.22-1.37 and 1.16, 95% CI: 1.11-1.21 by CVAI and VAI) and composite endpoint of new DM and death among those without baseline DM.Conclusions:Our population-based data demonstrated that Chinese visceral adiposity index may serve as a superior clinical indicator of diabetes when compared with conventional anthropometric indices among older adult Chinese, especially in women.
