PIWI-clade proteins harness pi RNAs of 24–33 nt in length.Of great puzzles are how PIWI-clade proteins incorporate pi RNAs of different sizes and whether the size matters to PIWI/pi RNA function.Here we report that a...PIWI-clade proteins harness pi RNAs of 24–33 nt in length.Of great puzzles are how PIWI-clade proteins incorporate pi RNAs of different sizes and whether the size matters to PIWI/pi RNA function.Here we report that a PIWI-Ins module unique in PIWIclade proteins helps define the length of pi RNAs.Deletion of PIWI-Ins in Miwi shifts MIWI to load with shorter pi RNAs and causes spermiogenic failure in mice,demonstrating the functional importance of this regulatory module.Mechanistically,we show that longer pi RNAs provide additional complementarity to target m RNAs,thereby enhancing the assembly of the MIWI/e IF3f/Hu R super-complex for translational activation.Importantly,we identify a c.1108C>T(p.R370W)mutation of HIWI(human PIWIL1)in infertile men and demonstrate in Miwi knock-in mice that this genetic mutation impairs male fertility by altering the property of PIWI-Ins in selecting longer pi RNAs.These findings reveal a critical role of PIWI-Ins-ensured longer pi RNAs in fine-tuning MIWI/pi RNA targeting capacity,proven essential for spermatid development and male fertility.展开更多
Ischemic stroke is a severe disorder resulting from acute cerebral thrombosis.Here we demonstrated that post-ischemic treatment with ciclopirox olamine(CPX),a potent antifungal clinical drug,alleviated brain infarctio...Ischemic stroke is a severe disorder resulting from acute cerebral thrombosis.Here we demonstrated that post-ischemic treatment with ciclopirox olamine(CPX),a potent antifungal clinical drug,alleviated brain infarction,neurological deficits and brain edema in a classic rat model of ischemic stroke.Single dose post-ischemic administration of CPX provided a long-lasting neuroprotective effect,which can be further enhanced by multiple doses administration of CPX.CPX also effectively reversed ischemia-induced neuronal loss,glial activation as well as blood-brain barrier(BBB)damage.Employing quantitative phosphoproteomic analysis,130 phosphosites in 122 proteins were identified to be significantly regulated by CPX treatment in oxygen glucose deprivation(OGD)-exposed SH-SY5 Y cells,which revealed that phosphokinases and cell cycle-related phosphoproteins were largely influenced.Subsequently,we demonstrated that CPX markedly enhanced the AKT(protein kinase B,PKB/AKT)and GSK3β(glycogen synthase kinase 3β)phosphorylation in OGD-exposed SH-SY5 Y cells,and regulated the cell cycle progression and nitric oxide(NO)release in lipopolysaccharide(LPS)-induced B V-2 cells,which may contribute to its ameliorative effects against ischemia-associated neuronal death and microglial inflammation.Our study suggests that CPX could be a promising compound to reduce multiple ischemic injuries;however,further studies will be needed to clarify the molecular mechanisms involved.展开更多
Autophagy is the main catabolic pathway in cells for the degradation of impaired proteins and organelles. Accumulating evidence supports the hypothesis that dysfunction of autophagy, leading to an imbalance of proteos...Autophagy is the main catabolic pathway in cells for the degradation of impaired proteins and organelles. Accumulating evidence supports the hypothesis that dysfunction of autophagy, leading to an imbalance of proteostasis and the accumulation of toxic proteins in neurons, is a central player in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis(ALS). The clinical pathology of ALS is complex and many genes associated with autophagy and RNA processing are mutated in patients with the familial form. But a causal relationship between autophagic dysfunction and ALS has not been fully established. More importantly, studies on the pathological mechanism of ALS are mainly based on animal models that may not precisely recapitulate the disease itself in human beings. The development of human iPSC techniques allows us to address these issues directly in human cell models that may profoundly influence drug discovery for ALS.展开更多
基金supported by the National Key Research and Development Program of China(2022YFA1303300,2021YFC2700200,2017YFA0504400)Chinese Academy of Sciences(“Strategic Priority Research Program”grants XDB37000000)+3 种基金the National Natural Science Foundation of China(31830109,31821004,91940305,31961133022,32101037,32271347,21933010,22203089)Science and Technology Commission of Shanghai Municipality(17JC1420100,2017SHZDZX01,19JC1410200,21YF1452700,21ZR1470500)the Young Elite Scientist Sponsorship Program of the China Association for Science and Technology(2021QNRC001)the Foundation of Key Laboratory of Gene Engineering of the Ministry of Education。
文摘PIWI-clade proteins harness pi RNAs of 24–33 nt in length.Of great puzzles are how PIWI-clade proteins incorporate pi RNAs of different sizes and whether the size matters to PIWI/pi RNA function.Here we report that a PIWI-Ins module unique in PIWIclade proteins helps define the length of pi RNAs.Deletion of PIWI-Ins in Miwi shifts MIWI to load with shorter pi RNAs and causes spermiogenic failure in mice,demonstrating the functional importance of this regulatory module.Mechanistically,we show that longer pi RNAs provide additional complementarity to target m RNAs,thereby enhancing the assembly of the MIWI/e IF3f/Hu R super-complex for translational activation.Importantly,we identify a c.1108C>T(p.R370W)mutation of HIWI(human PIWIL1)in infertile men and demonstrate in Miwi knock-in mice that this genetic mutation impairs male fertility by altering the property of PIWI-Ins in selecting longer pi RNAs.These findings reveal a critical role of PIWI-Ins-ensured longer pi RNAs in fine-tuning MIWI/pi RNA targeting capacity,proven essential for spermatid development and male fertility.
基金supported by the National Natural Science Foundation of China(Nos.81872859,81661148046,81522045,and 81703507)the National Special Fund for State Key Laboratory of Bioreactor Engineering(No.2060204,China)+1 种基金the National R&D Projects for major research instruments(ZDYZ2013-1,China)the Institutional Technology Service Center of Shanghai Institute of Materia Medica,Chinese Academy of Sciences for technical support.
文摘Ischemic stroke is a severe disorder resulting from acute cerebral thrombosis.Here we demonstrated that post-ischemic treatment with ciclopirox olamine(CPX),a potent antifungal clinical drug,alleviated brain infarction,neurological deficits and brain edema in a classic rat model of ischemic stroke.Single dose post-ischemic administration of CPX provided a long-lasting neuroprotective effect,which can be further enhanced by multiple doses administration of CPX.CPX also effectively reversed ischemia-induced neuronal loss,glial activation as well as blood-brain barrier(BBB)damage.Employing quantitative phosphoproteomic analysis,130 phosphosites in 122 proteins were identified to be significantly regulated by CPX treatment in oxygen glucose deprivation(OGD)-exposed SH-SY5 Y cells,which revealed that phosphokinases and cell cycle-related phosphoproteins were largely influenced.Subsequently,we demonstrated that CPX markedly enhanced the AKT(protein kinase B,PKB/AKT)and GSK3β(glycogen synthase kinase 3β)phosphorylation in OGD-exposed SH-SY5 Y cells,and regulated the cell cycle progression and nitric oxide(NO)release in lipopolysaccharide(LPS)-induced B V-2 cells,which may contribute to its ameliorative effects against ischemia-associated neuronal death and microglial inflammation.Our study suggests that CPX could be a promising compound to reduce multiple ischemic injuries;however,further studies will be needed to clarify the molecular mechanisms involved.
基金supported by the Ministry of Science and Technology of China (2011CB966200)the National Natural Science Foundation of China (81401053,31471029,81461138037,and 81472141)+2 种基金the National Program for Support of Top-notch Young Professionalsthe Program for Young Excellent Talents in Tongji University (2014KJ049)the Public Health Bureau of Tianjin Municipality,China (13KG127)
文摘Autophagy is the main catabolic pathway in cells for the degradation of impaired proteins and organelles. Accumulating evidence supports the hypothesis that dysfunction of autophagy, leading to an imbalance of proteostasis and the accumulation of toxic proteins in neurons, is a central player in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis(ALS). The clinical pathology of ALS is complex and many genes associated with autophagy and RNA processing are mutated in patients with the familial form. But a causal relationship between autophagic dysfunction and ALS has not been fully established. More importantly, studies on the pathological mechanism of ALS are mainly based on animal models that may not precisely recapitulate the disease itself in human beings. The development of human iPSC techniques allows us to address these issues directly in human cell models that may profoundly influence drug discovery for ALS.
