TFE3

撰文丨王聪 编辑丨王多鱼 排版丨水成文 固有免疫是宿主抵御病原体的第一道防线。在哺乳动物细胞中，模式识别受体（PRR）检测微生物成分并触发固有免疫应答。作为细胞内的PRR， cGAS识别细胞质中的微生物或宿主来源的DNA并产生cGAMP， cGAMP与STING结合并导致STING从内质网输出。 诱导自噬是cGAS-STING通路的一个古老功能，通过该通路，自噬货物被运送到溶酶体降解。然而，溶酶体本身的功能是否也受到cGAS-STING通路的调节，目前尚不清楚。 2024年12月16日，浙江大学医学院附属邵逸夫医院万伟研究员、浙江大学国际健康研究院刘伟教授及湖南第一师范学院许银丰副教授等，在 Immunity 期刊发表了题为：The cGAS-STING pathway activates transcription factor TFEB to stimulate lysosome biogenesis and pathogen clearance 的研究论文。 该研究表明，cGAS-STING通路激活转录因子TFEB，刺激溶酶体生物发生和病原体清除，从而揭示了cGAS-STING通路的一个新的重要功能——诱导溶酶体生物发生。 在这项最新研究中，研究团队发现，cGAS-STING通路通过独立于其下游蛋白激酶TANK结合激酶1（TBK1）的溶酶体生物发生过程，来上调溶酶体活性。 STING的激活通过诱导转录因子EB（TFEB）及其同源转录因子TFE3和MITF的核转位，来增强溶酶体的生物发生。STING的诱导GABA A型受体相关蛋白（GABARAP）脂质化，这是一种自噬相关蛋白，位于STING囊泡上，负责TFEB的激活。 膜结合的GABARAP隔离了GTP酶激活蛋白卵巢滤泡激素（FLCN）和FLCN相互作用蛋白（FNIP）复合体，以阻止其对RagC和RagD的功能，解除了mTORC1依赖的磷酸化和TFEB失活。 在功能上，STING诱导的细胞内溶酶体生物发生促进了胞质DNA和入侵病原体的清除。因此，这些发现揭示了诱导溶酶体生物发生是cGAS-STING通路的另一个重要功能。 该研究的核心发现： cGAS-STING通路可增强溶酶体活性； STING的激活足以激活TFEB，从而刺激溶酶体的生物发生； STING诱导的GABARAP脂质化介导TFEB激活； STING诱导的溶酶体生物发生有助于病原体的清除； 论文链接： https://www.cell.com/immunity/abstract/S1074-7613(24)00532-6 设置星标，不错过精彩推文 开放转载 欢迎转发到朋友圈和微信群  微信加群  为促进前沿研究的传播和交流，我们组建了多个专业交流群，长按下方二维码，即可添加小编微信进群，由于申请人数较多，添加微信时请备注：学校/专业/姓名，如果是PI/教授，还请注明。 点在看，传递你的品味

▎药明康德内容团队编辑（来源：良渚实验室） 全能性是指细胞具有分化形成完整个体的分化潜能。在小鼠中，受精后形成的合子与二细胞期胚胎具有严格意义上的全能性，而胚胎在进入四细胞时期后将逐渐退出全能性。 胚胎全能性发育过程中伴随着一系列特异性的分子事件，如核子基因组激活等。值得注意的是，许多全能性时期特异性表达的转录本，如Zscan4、内源逆转录病毒MERVL/MT2_Mm等，会在胚胎退出全能性时快速下调。这些转录本的下调对于胚胎退出全能性以及正常发育起到重要作用，但下调的具体分子机制尚未完全揭示。 近日，良渚实验室研究员傅旭东团队在Developmental Cell上发表了题为Lysosomal catabolic activity promotes the exit of murine totipotent 2-cell state by silencing early-embryonic retrotransposons的研究论文，该研究利用全能性体外研究模型二细胞样细胞（2CLCs），阐明了溶酶体代谢活性可以通过抑制全能性相关的内源逆转录病毒MERVL/MT2_Mm的转录，促进胚胎退出全能性的新功能。  该团队首先发现小鼠胚胎干细胞进入二细胞样状态（类全能性状态）时溶酶体活性下降，同时溶酶体抑制剂处理促进小鼠胚胎干细胞进入二细胞样状态，并且提高了二细胞样状态的稳定性。这些结果表明溶酶体活性可以在小鼠胚胎干细胞中起到抑制全能性状态的功能。 进一步研究发现，溶酶体活性主要通过影响细胞氨基酸浓度去调控全能性。当溶酶体活性增高时，细胞氨基酸浓度上升，并激活下游RagC/D的活性。RagC/D定位于溶酶体膜上，可通过感知细胞内的氨基酸浓度，调控下游转录因子（如TFEB、TFE3）的活性，影响细胞转录。 ▲转录因子TFEB/3在细胞进入全能性后结合并激活内源逆转录病毒MERVL/MT2_Mm（图片来源：原始论文[1]） 该团队发现，RagC/D激活时，TFEB、TFE3会被招募之细胞质并失活，从而促进全能性特异性转录本（如Zscan4）的下调以及全能性退出。而当溶酶体活性被抑制时，细胞氨基酸浓度下降，RagC/D随之失活，导致TFEB/TFE3进入细胞核，并促进全能性特异性转录本的上调以及抑制细胞退出全能性。 转录因子TFEB/TFE3传统转录调控靶点主要是溶酶体代谢相关基因。但本研究通过CUT&Tag测序分析，发现在全能性状态下，TFEB/TFE3在全能性相关的内源逆转录病毒MERVL/MT2_Mm基因组位点的结合水平增加，并激活这些逆转录病毒的转录，从而影响全能性特异性转录本的表达以及细胞全能性。 进一步的数据表明，TFEB/TFE3在MERVL/MT2_Mm基因组位点的结合，主要由MERVL/MT2_Mm的5’端LTR序列的CLEAR moif介导。 ▲溶酶体活性通过抑制小鼠内源逆转录病毒MERVL/MT2_Mm促进胚胎与细胞退出全能性（图片来源：原始论文[1]） 该研究同时发现，在小鼠胚胎发育中，溶酶体代谢活性也通过影响胚胎氨基酸浓度调控胚胎全能性的退出。具体结果指出，在小鼠早期胚胎发育过程中，溶酶体代谢活性在胚胎二细胞晚期显著上调。 溶酶体活性促进了胚胎内的氨基酸浓度上升，并通过RagC介导了TFE3退出细胞核，抑制了MERVL/MT2_Mm的转录，从而促进全能性特异转录本的下调，以及胚胎退出全能性。而溶酶体抑制剂、抑制RagC活性或转录因子TFE3过表达，均导致小鼠胚胎在二细胞期阻滞，并抑制了全能性特异性转录本的下调。 综上所述，该研究证明溶酶体代谢活性参与了小鼠细胞全能性的调控。溶酶体活性通过影响细胞氨基酸浓度，抑制了二细胞胚胎的内源逆转录病毒的转录，促进了二细胞胚胎中全能性特异性转录本的下调，并促进二细胞胚胎退出全能性。 良渚实验室傅旭东研究员为本论文通讯作者，博士生吴昊与博士后曹兰蕊为本论第一作者。良渚实验室及浙江大学医学院附属第一医院为本论文第一与通讯作者单位。该论文参与作者包括良渚实验室徐浩新教授、张进教授，浙江大学叶存奇研究员、张银丽研究员，以及清华大学颉伟教授、博士后嵇姝妍等。该研究还得到了哈佛大学张毅教授、浙江大学刘冲教授、良渚实验室沈宁研究员的指导与帮助。 原始论文： [1]Lysosomal catabolic activity promotes the exit of murine totipotent 2-cell state by silencing early-embryonic retrotransposons. Nat Commun 15, 10012 (2024). https://doi.org/10.1038/s41467-024-54374-z 免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。 更多推荐 点个“在看”再走吧~

MIPLYFFA, the first FDA-approved treatment for Niemann-Pick disease type C, is available at Zevra’s specialty pharmacy for dispense AmplifyAssist™, Zevra’s comprehensive patient support program, in place to address access barriers Nov. 21, 2024 -- Zevra Therapeutics, Inc. (NasdaqGS: ZVRA) (Zevra, or the Company), a commercial-stage rare disease therapeutics company, today announced that MIPLYFFA™ (MY-PLY-FAH) (arimoclomol), the first treatment approved by the U.S. Food and Drug Administration (FDA) for the treatment of Nieman Pick disease type C (NPC), is now commercially available for dispense. MIPLYFFA is indicated for use in combination with miglustat for the treatment of neurological manifestations of NPC in adult and pediatric patients 2 years of age and older. “Early adoption of MIPLYFFA has exceeded our expectations, and we are pleased to report that product is now available for shipment to NPC patients. This is in line with the shorter timeframe of our guidance of eight to 12 weeks post-approval,” said Josh Schafer, Chief Commercial Officer and Executive Vice President of Business Development, Zevra Therapeutics. “We continue to receive prescription enrollments through our patient services program, AmplifyAssist, and are supporting patients as they navigate the benefits verification process to obtain MIPLYFFA.” AmplifyAssist is Zevra’s comprehensive patient support program designed to support the individual needs of eligible patients and those who care for them. Available resources include personalized insurance coverage education and support, copay and alternate funding identification assistance for eligible patients’ product needs, disease state information and therapy management counseling, and ongoing interactions to address barriers while facilitating timely prescription refills. Information about the program is available at MIPLYFFA.com or via telephone. The AmplifyAssist team can be reached toll-free at (888) 668-4198 from 8 a.m. CT to 6 p.m. CT Monday through Friday. Patients and caregivers should speak with their physician to get started with MIPLYFFA. Physicians can fill out an enrollment form at MIPLYFFA.com, order the prescription, and when approved, the medication will be mailed to their patient’s home. Healthcare providers and patients/caregivers should refer to the Full Prescribing Information and Instructions for Use for information on the proper administration of MIPLYFFA. Zevra is committed to assisting those whose lives are affected by NPC to overcome the barriers and challenges that may impact their treatment journey. AmplifyAssist is Zevra’s comprehensive patient support program. The mission of the program is to support the individual needs of eligible patients and those who care for them. Available resources include personalized insurance coverage education and support, copay and alternate funding identification assistance for eligible patients’ product needs, disease state information and therapy management counseling, and ongoing interactions to address barriers while facilitating timely prescription refills. Information about the program is available at MIPLYFFA.com or via telephone. The AmplifyAssist team can be reached toll-free at (888) 668-4198 from 8 a.m. CT to 6 p.m. CT Monday through Friday. Healthcare providers who want to submit prescriptions can visit MIPLYFFA.com to complete the prescription enrollment form that initiates the process for accessing the treatment. MIPLYFFA (arimoclomol) increases the activation of the transcription factors EB (TFEB) and E3 (TFE3) resulting in the upregulation of coordinated lysosomal expression and regulation (CLEAR) genes. MIPLYFFA has also been shown to reduce unesterified cholesterol in the lysosomes of human NPC fibroblasts. The clinical significance of these findings is not fully understood. In the pivotal phase 3 trial, MIPLYFFA halted disease progression compared to placebo over the one-year duration of the trial when measured by the only validated disease progression measurement tool, the NPC Clinical Severity Scale. MIPLYFFA was granted Breakthrough Therapy designation, Rare Pediatric Disease designation, Orphan Drug designation, and Fast Track designation by the FDA for the treatment of NPC. MIPLYFFA was further granted Orphan Medicinal Product designation by the European Medicines Agency (EMA) for the treatment of NPC. Niemann-Pick disease type C (NPC) is an ultra-rare, progressive, and neurodegenerative lysosomal storage disorder characterized by an inability of the body to transport cholesterol and other lipids within the cell, leading to an accumulation of these substances in various cell types, including neurons. The disease is caused by mutations in the NPC1 or NPC2 genes, which are responsible for making the NPC1 and NPC2 lysosomal proteins. Both children and adults can be affected by NPC with varying clinical presentations. Those living with NPC can lose independence due to physical and cognitive limitations, with key neurological impairments presenting in speech, cognition, swallowing, ambulation, and fine motor skills. Disease diagnosis can often take years, with disease progression being irreversible and often leading to early mortality. Zevra Therapeutics, Inc. is a commercial-stage rare disease company combining science, data, and patient needs to create transformational therapies for diseases with limited or no treatment options. Our mission is to bring life-changing therapeutics to people living with rare diseases. With unique, data-driven development and commercialization strategies, the Company is overcoming complex drug development challenges to make new therapies available to the rare disease community. Expanded access programs are made available by Zevra Therapeutics, Inc. and its affiliates and are subject to the Company's Expanded Access Program (EAP) policy, as published on its website. Participation in these programs is subject to the laws and regulations of each jurisdiction under which each respective program is operated. Eligibility for participation in any such program is at the treating physician's discretion. The content above comes from the network. if any infringement, please contact us to modify.