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| 1 | Hyperthermia promotes degradation of the acute promyelocytic leukemia driver oncoprotein ZBTB16/RARα显示文摘The acute promyelocytic leukemia(APL)driver ZBTB16/RARαis generated by the t(11;17)(q23;q21)chromosomal translocation,which is resistant to combined treatment of all-trans retinoic acid(ATRA)and arsenic trioxide(ATO)or conventional chemotherapy,resulting in extremely low survival rates.In the current study,we investigated the effects of hyperthermia on the oncogenic fusion ZBTB16/RARαprotein to explore a potential therapeutic approach for this variant APL.We showed that Z/R fusion protein expressed in HeLa cells was resistant to ATO,ATRA,and conventional chemotherapeutic agents.However,mild hyperthermia(42℃)rapidly destabilized the ZBTB16/RARαfusion protein expressed in HeLa,293T,and OCI-AML3 cells,followed by robust ubiquitination and proteasomal degradation.In contrast,hyperthermia did not affect the normal(i.e.,unfused)ZBTB16 and RARαproteins,suggesting a specific thermal sensitivity of the ZBTB16/RARαfusion protein.Importantly,we found that the destabilization of ZBTB16/RARαwas the initial step for oncogenic fusion protein degradation by hyperthermia,which could be blocked by deletion of nuclear receptor corepressor(NCoR)binding sites or knockdown of NCoRs.Furthermore,SIAH2 was identified as the E3 ligase participating in hyperthermia-induced ubiquitination of ZBTB16/RARα.In short,these results demonstrate that hyperthermia could effectively destabilize and subsequently degrade the ZBTB16/RARαfusion protein in an NCoR-dependent manner,suggesting a thermal-based therapeutic strategy that may improve the outcome in refractory ZBTB16/RARα-driven APL patients in the clinic. | Qian-qian Wang Liaqat Hussain Pei-han Yu Chang Yang Chen-ying Zhu Ya-fang Ma Si-chun Wang Tao Yang Yuan-yuan Kang Wen-juan Yu Yasen Maimaitiyiming Hua Naranmandura | 2023 | Acta Pharmacologica Sinica2023，44，4： | 1 |
| 2 | Heat Treatment Promotes Ubiquitin-Mediated Proteolysis of SARS-CoV-2 RNA Polymerase and Decreases Viral Load显示文摘Despite extensive eforts,COVID-19 pandemic caused by the SARS-CoV-2 virus is still at large.Vaccination is an eftive approach to curb virus spread,but several variants(eg.delta,delta plus,omicron,and IHU)appear to weaken or possibly escape immune protection.Thus,novel and quickly scalable approaches to restrain SARS-CoV-2 are urgently needed.Mutiple evidences showed thermal sensitivity of SARS-CoV-2 and negative correlation between environmental temperature and COVID-19 transmission with unknown mechanism.Here.we reveal a potential mechanism by which mild heat treatment destabilizes the wild-type RNA-dependent RNA polymerase(also known a nonstructural protein 12(NSP12))of SARS-CoV-2 as well as the P323L mutant commonly found in SARS-CoV-2 variants,including omicron and IHU.Mechanistically,heat treatment promotes E3 ubiquitin ligase ZNF598-dependent NSP12 ubiquitination leading to proteasomal degradation and significantly decreases SARS-CoV-2 RNA copy number and viral titer.A mild daily heat Ireatment maintains low levels of both wild-type and P323L mutant of NSP12,sugesting clinical potential.Collctivel',this novel mechanism,heat-induced NSP12 degradation,suggests a prospective heat-based intervention against SARS-CoV-2. | Yasen Maimaitiyiming Tao Yang Qian Qian Wang Yan Feng Zhi Chen Mikael Bjorklund Fudi Wang Chonggao Hu Chih-Hung Hsu Hua Naranmandura | 2022 | Research2022，，2： | 1 |
| 3 | YTHDF2-mediated regulations bifurcate BHPF-induced programmed cell deaths显示文摘N6-methyladenosine(m^(6)A)is a critical regulator in the fate of RNA,but whether and how m^(6)A executes its functions in different tissues remains largely obscure.Here we report downregulation of a crucial m^(6)A reader,YTHDF2,leading to tissue-specific programmed cell deaths(PCDs)upon fluorene-9-bisphenol(BHPF)exposure.Currently,Bisphenol A(BPA)substitutes are widely used in plastic manufacturing.Interrogating eight common BPA substitutes,we detected BHPF in 14%serum samples of pregnant participants.In a zebrafish model,BHPF caused tissue-specific PCDs triggering cardiac and vascular defects.Mechanistically,BHPF-mediated downregulation of YTHDF2 reduced YTHDF2-facilitated translation of m^(6)A-gch1 for cardiomyocyte ferroptosis,and decreased YTHDF2-mediated m^(6)A-sting1 decay for caudal vein plexus(CVP)apoptosis.The two distinct YTHDF2-mediated m^(6)A regulations and context-dependent co-expression patterns of gch1/ythdf2 and tnfrsf1a/ythdf2 contributed to YTHDF2-mediated tissue-specific PCDs,uncovering a new layer of PCD regulation.Since BHPF/YTHDF2-medaited PCD defects were also observed in mammals,BHPF exposure represents a potential health threat. | Jiebo Lin Guankai Zhan Jinfeng Liu Yasen Maimaitiyiming Zhiping Deng Baohua Li Kunhui Su Jiafeng Chen Siqi Sun Wanlin Zheng Xianghui Yu Feng He Xiaodong Cheng Lingfang Wang Bin Shen Ziqin Yao Xinquan Yang Jian Zhang Wentao He Hengyu Wu Hua Naranmandura Kao-Jung Chang Junxia Min Jun Ma Mikael Björklund Peng-Fei Xu Fudi Wang Chih-Hung Hsu | 2023 | National Science Review2023，10，12： | 0 |
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