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Deciphering transcription activity of mammalian early embryos unveils on/off of zygotic genome activation by protein translation/degradation.
IF 7.5 1区 生物学
Cell reports Pub Date : 2025-01-16 DOI: 10.1016/j.celrep.2024.115215
Yi-Ran Zhang, Shi-Meng Guo, Xiao-Yan Shi, Yi-Wen Ding, Huai-Biao Li, Lei Li, Jia-Wei Xu, Ximiao He, Bing-Xin Ma, Ying Yin, Li-Quan Zhou
{"title":"Deciphering transcription activity of mammalian early embryos unveils on/off of zygotic genome activation by protein translation/degradation.","authors":"Yi-Ran Zhang, Shi-Meng Guo, Xiao-Yan Shi, Yi-Wen Ding, Huai-Biao Li, Lei Li, Jia-Wei Xu, Ximiao He, Bing-Xin Ma, Ying Yin, Li-Quan Zhou","doi":"10.1016/j.celrep.2024.115215","DOIUrl":"https://doi.org/10.1016/j.celrep.2024.115215","url":null,"abstract":"<p><p>Quantification of transcription activities in mammalian preimplantation embryos is challenging due to a huge amount of maternally stored transcripts and paucity of research materials. Here, we investigate genome-wide transcription activities of mouse and human preimplantation embryos by quantifying elongating RNA polymerase II. Two transcriptional waves are identified in early mouse embryos, with summits at the 2-cell and 8-cell stages. Gene collections with different expression patterns are obtained, with genes mainly transcribed at the mouse early/late 2-cell stage designated as zygotic genome activation-early/late 2-cell (ZGA-E2C/L2C). ZGA-E2C genes are short and have low promoter CpG density. Protein translation/degradation not only regulates transcription activity through stepwise orchestration of histone modifications, transcriptional initiation, and elongation in early mouse embryos but also controls on/off switching of ZGA-E2C/L2C genes in maternal aged mouse embryos. Genes mainly transcribed at the mouse 2-cell stage can also be transcribed as early as the human 2-cell stage.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 1","pages":"115215"},"PeriodicalIF":7.5,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000721","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
ERF114/115/109 are essential for jasmonate-repressed non-canonical JAZ8 activity in JA signaling.
IF 7.5 1区 生物学
Cell reports Pub Date : 2025-01-16 DOI: 10.1016/j.celrep.2024.115222
Jiaxuan Sui, Qianlan Yin, Yiying Chen, Min Sun, Xianzheng Yuan, Zhaojun Ding, Xiangpei Kong
{"title":"ERF114/115/109 are essential for jasmonate-repressed non-canonical JAZ8 activity in JA signaling.","authors":"Jiaxuan Sui, Qianlan Yin, Yiying Chen, Min Sun, Xianzheng Yuan, Zhaojun Ding, Xiangpei Kong","doi":"10.1016/j.celrep.2024.115222","DOIUrl":"https://doi.org/10.1016/j.celrep.2024.115222","url":null,"abstract":"<p><p>Jasmonate (JA), a key plant hormone, regulates various aspects of plant development and stress responses, primarily through the degradation of canonical jasmonate-ZIM domain (JAZ) proteins by the SCF<sup>COI1</sup> complex. While JAZ8, a non-canonical JAZ protein lacking the degron signal, has been shown to repress JA responses, the mechanism by which JA inhibits JAZ8 activity remains unclear. Here, we demonstrate that Arabidopsis ethylene response factor 114 (ERF114), ERF115, and ERF109 regulate JA signaling through interacting with JAZ8. This interaction disrupts the formation of the MYC2/3/4-JAZ8 and root hair defective 6 (RHD6)-JAZ8 complexes. We show that ERF114 positively regulates JA-induced transcriptional responses and that JA-promoted root hair growth is highly alleviated in erf114 mutants. Furthermore, the transcription of ERF114/115/109 is induced by JA in an MYC2-dependent manner, thus forming a positive feedback loop in JA signaling. Collectively, this study reveals a regulatory pathway in which ERF114/115/109 regulate JA signaling by targeting non-canonical JAZ proteins.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 1","pages":"115222"},"PeriodicalIF":7.5,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000745","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Lack of context modulation in human single neuron responses in the medial temporal lobe.
IF 7.5 1区 生物学
Cell reports Pub Date : 2025-01-15 DOI: 10.1016/j.celrep.2024.115218
Hernan G Rey, Theofanis I Panagiotaropoulos, Lorenzo Gutierrez, Fernando J Chaure, Alejandro Nasimbera, Santiago Cordisco, Fabian Nishida, Antonio Valentin, Gonzalo Alarcon, Mark P Richardson, Silvia Kochen, Rodrigo Quian Quiroga
{"title":"Lack of context modulation in human single neuron responses in the medial temporal lobe.","authors":"Hernan G Rey, Theofanis I Panagiotaropoulos, Lorenzo Gutierrez, Fernando J Chaure, Alejandro Nasimbera, Santiago Cordisco, Fabian Nishida, Antonio Valentin, Gonzalo Alarcon, Mark P Richardson, Silvia Kochen, Rodrigo Quian Quiroga","doi":"10.1016/j.celrep.2024.115218","DOIUrl":"https://doi.org/10.1016/j.celrep.2024.115218","url":null,"abstract":"<p><p>In subjects implanted with intracranial electrodes, we use two different stories involving the same person (or place) to evaluate whether and to what extent context modulates human single-neuron responses. Nearly all neurons (97% during encoding and 100% during recall) initially responding to a person/place do not modulate their response with context. Likewise, nearly none (<1%) of the initially non-responsive neurons show conjunctive coding, responding to particular persons/places in a particular context during the tasks. In line with these findings, taking all neurons together it is possible to decode the person/place being depicted in each story, but not the particular story. Moreover, the neurons show consistent results across encoding and recall of the stories and during passive viewing of pictures. These results suggest a context invariant, non-conjunctive coding of memories at the single-neuron level in the human hippocampus and amygdala, in contrast to what has been described in other species.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 1","pages":"115218"},"PeriodicalIF":7.5,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000772","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Coordinated neuron-specific splicing events restrict nucleosome engagement of the LSD1 histone demethylase complex.
IF 7.5 1区 生物学
Cell reports Pub Date : 2025-01-15 DOI: 10.1016/j.celrep.2024.115213
Robert S Porter, Sojin An, Maria C Gavilan, Masayoshi Nagai, Yumie Murata-Nakamura, Bo Zhou, Katherine M Bonefas, Olivier Dionne, Jeru Manoj Manuel, Joannie St-Germain, Suzanne Gascon, Jacqueline Kim, Liam Browning, Benoit Laurent, Uhn-Soo Cho, Shigeki Iwase
{"title":"Coordinated neuron-specific splicing events restrict nucleosome engagement of the LSD1 histone demethylase complex.","authors":"Robert S Porter, Sojin An, Maria C Gavilan, Masayoshi Nagai, Yumie Murata-Nakamura, Bo Zhou, Katherine M Bonefas, Olivier Dionne, Jeru Manoj Manuel, Joannie St-Germain, Suzanne Gascon, Jacqueline Kim, Liam Browning, Benoit Laurent, Uhn-Soo Cho, Shigeki Iwase","doi":"10.1016/j.celrep.2024.115213","DOIUrl":"https://doi.org/10.1016/j.celrep.2024.115213","url":null,"abstract":"<p><p>Chromatin regulatory proteins are expressed broadly and assumed to exert the same intrinsic function across cell types. Here, we report that 14 chromatin regulators undergo evolutionary-conserved neuron-specific splicing events involving microexons. Among them are two components of a histone demethylase complex: LSD1 H3K4 demethylase and the H3K4me0-reader PHF21A. We found that neuronal LSD1 splicing reduces the enzymes' affinity to the nucleosome. Meanwhile, neuronal PHF21A splicing significantly attenuates histone H3 binding and further ablates the DNA-binding function exerted by an AT-hook motif. Furthermore, in vitro reconstitution of the canonical and neuronal PHF21A-LSD1 complexes, combined with in vivo methylation mapping, identified the neuronal complex as a hypomorphic H3K4 demethylating machinery. The neuronal PHF21A, albeit with its weaker nucleosome binding, is necessary for normal gene expression and the H3K4 landscape in the developing brain. Thus, ubiquitously expressed chromatin regulatory complexes can exert neuron-specific functions via alternative splicing of their subunits.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 1","pages":"115213"},"PeriodicalIF":7.5,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000708","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Single cell approaches define neural stem cell niches and identify microglial ligands that can enhance precursor-mediated oligodendrogenesis.
IF 7.5 1区 生物学
Cell reports Pub Date : 2025-01-15 DOI: 10.1016/j.celrep.2024.115194
Ashleigh Willis, Danielle Jeong, Yunlong Liu, Marissa A Lithopoulos, Scott A Yuzwa, Paul W Frankland, David R Kaplan, Freda D Miller
{"title":"Single cell approaches define neural stem cell niches and identify microglial ligands that can enhance precursor-mediated oligodendrogenesis.","authors":"Ashleigh Willis, Danielle Jeong, Yunlong Liu, Marissa A Lithopoulos, Scott A Yuzwa, Paul W Frankland, David R Kaplan, Freda D Miller","doi":"10.1016/j.celrep.2024.115194","DOIUrl":"https://doi.org/10.1016/j.celrep.2024.115194","url":null,"abstract":"<p><p>Here, we used single cell RNA sequencing and single cell spatial transcriptomics to characterize the forebrain neural stem cell (NSC) niche under homeostatic and injury conditions. We defined the dorsal and lateral ventricular-subventricular zones (V-SVZs) as two distinct neighborhoods and showed that, after white matter injury, NSCs are activated to make oligodendrocytes dorsally for remyelination. This activation is coincident with an increase in transcriptionally distinct microglia in the dorsal V-SVZ niche. We modeled ligand-receptor interactions within this changing niche and identified two remyelination-associated microglial ligands, insulin growth factor 1 and oncostatin M, that promote precursor proliferation and oligodendrogenesis in culture. Infusion of either ligand into the lateral ventricles also enhanced oligodendrogenesis, even in the lateral V-SVZ, where NSCs normally make neuroblasts. These data support a model where gliogenesis versus neurogenesis is determined by the local NSC neighborhood and where injury-induced niche alterations promote NSC activation, local oligodendrogenesis, and likely contribute to myelin repair.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 1","pages":"115194"},"PeriodicalIF":7.5,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000833","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Antigen affinity and site of immunization dictate B cell recall responses.
IF 7.5 1区 生物学
Cell reports Pub Date : 2025-01-15 DOI: 10.1016/j.celrep.2024.115221
Manon Termote, Rafael C Marques, Erik Hyllner, Mariia V Guryleva, Mirthe Henskens, Andreas Brutscher, Isabel J L Baken, Xaquin Castro Dopico, Adria Dalmau Gasull, Ben Murrell, Leonidas Stamatatos, Lisa S Westerberg, Pia Dosenovic
{"title":"Antigen affinity and site of immunization dictate B cell recall responses.","authors":"Manon Termote, Rafael C Marques, Erik Hyllner, Mariia V Guryleva, Mirthe Henskens, Andreas Brutscher, Isabel J L Baken, Xaquin Castro Dopico, Adria Dalmau Gasull, Ben Murrell, Leonidas Stamatatos, Lisa S Westerberg, Pia Dosenovic","doi":"10.1016/j.celrep.2024.115221","DOIUrl":"https://doi.org/10.1016/j.celrep.2024.115221","url":null,"abstract":"<p><p>Protective antibodies against HIV-1 require unusually high levels of somatic mutations introduced in germinal centers (GCs). To achieve this, a sequential vaccination approach was proposed. Using HIV-1 antibody knockin mice with fate-mapping genes, we examined if antigen affinity affects the outcome of B cell recall responses. Compared to a high-affinity boost, a low-affinity boost resulted in decreased numbers of memory-derived B cells in secondary GCs but with higher average levels of somatic mutations, indicating an affinity threshold for memory B cells to enter GCs. Furthermore, upon boosting local lymph nodes (LNs), the composition of primary GCs was modified in an antigen-affinity-dependent manner to constitute less somatically mutated B cells. Our results demonstrate that antigen affinity and location of the boost affect the outcome of the B cell recall response. These results can help guide the design of vaccine immunogens aiming to selectively engage specific B cell clones for further diversification.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 1","pages":"115221"},"PeriodicalIF":7.5,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000607","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Menin orchestrates macrophage reprogramming to maintain the pulmonary immune homeostasis.
IF 7.5 1区 生物学
Cell reports Pub Date : 2025-01-15 DOI: 10.1016/j.celrep.2024.115219
Xingwen Zhu, Bin Xu, Aobo Lian, Xiaoqian Zhang, Yiting Wang, Yuan Zhang, Li Zhang, Jie Ma, Shubin Gao, Guanghui Jin
{"title":"Menin orchestrates macrophage reprogramming to maintain the pulmonary immune homeostasis.","authors":"Xingwen Zhu, Bin Xu, Aobo Lian, Xiaoqian Zhang, Yiting Wang, Yuan Zhang, Li Zhang, Jie Ma, Shubin Gao, Guanghui Jin","doi":"10.1016/j.celrep.2024.115219","DOIUrl":"https://doi.org/10.1016/j.celrep.2024.115219","url":null,"abstract":"<p><p>Menin is a scaffold protein encoded by the Men1 gene, and it interacts with a variety of chromatin regulators to activate or repress cellular processes. The potential importance of menin in immune regulation remains unclear. Here, we report that myeloid deletion of Men1 results in the development of spontaneous pulmonary alveolar proteinosis (PAP). This is strongly correlated with impaired development of alveolar macrophages (AM) through inactivation of the granulocyte-macrophage colony-stimulating factor (GM-CSF/CSF2) pathway caused by Men1 deficiency. Mechanistically, menin directly interacts with the SET domain containing 2 (SETD2) through the N-terminal domain (NTD) and Palm domains to maintain protein stability and chromatin recruitment. SETD2 and menin collectively maintain CSF2 expression through H3K36me3, which orchestrates AM reprogramming and pulmonary immune homeostasis. Targeting H3K36me3 remodeling mitigated the aberrant activation of macrophages caused by lipopolysaccharide (LPS). Our results point to a nonredundant role of menin in the control of macrophage lineage maintenance via reinforcement of the H3K36me3 transcriptional program.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 1","pages":"115219"},"PeriodicalIF":7.5,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000778","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Widespread innervation of motoneurons by spinal V3 neurons globally amplifies locomotor output in mice.
IF 7.5 1区 生物学
Cell reports Pub Date : 2025-01-15 DOI: 10.1016/j.celrep.2024.115212
Han Zhang, Dylan Deska-Gauthier, Colin S MacKay, Krishnapriya Hari, Ana M Lucas-Osma, Joanna Borowska-Fielding, Reese L Letawsky, Vladimir Rancic, Turgay Akay, Keith K Fenrich, David J Bennett, Ying Zhang
{"title":"Widespread innervation of motoneurons by spinal V3 neurons globally amplifies locomotor output in mice.","authors":"Han Zhang, Dylan Deska-Gauthier, Colin S MacKay, Krishnapriya Hari, Ana M Lucas-Osma, Joanna Borowska-Fielding, Reese L Letawsky, Vladimir Rancic, Turgay Akay, Keith K Fenrich, David J Bennett, Ying Zhang","doi":"10.1016/j.celrep.2024.115212","DOIUrl":"https://doi.org/10.1016/j.celrep.2024.115212","url":null,"abstract":"<p><p>While considerable progress has been made in understanding the neuronal circuits that underlie the patterning of locomotor behaviors, less is known about the circuits that amplify motoneuron output to adjust muscle force. Here, we demonstrate that propriospinal V3 neurons (Sim1<sup>+</sup>) account for ∼20% of excitatory input to motoneurons across hindlimb muscles. V3 neurons also form extensive connections among themselves and with other excitatory premotor neurons, such as V2a neurons. Optical activation of V3 neurons in a single segment rapidly amplifies locomotor-related motoneuron output at all lumbar segments in in vitro spinal cord and the awake adult mouse. Despite similar innervation from V3 neurons to flexor and extensor motoneuron pools, V3 neurons preferentially activate extensor muscles. Genetically or optogenetically silencing V3 neurons leads to slower and weaker mice with a reduced ability to adjust extensor muscle force. Thus, V3 neurons serve as global command neurons that amplify locomotion intensity.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 1","pages":"115212"},"PeriodicalIF":7.5,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000836","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Luminance invariant encoding in mouse primary visual cortex.
IF 7.5 1区 生物学
Cell reports Pub Date : 2025-01-15 DOI: 10.1016/j.celrep.2024.115217
Ronan T O'Shea, Ian Nauhaus, Xue-Xin Wei, Nicholas J Priebe
{"title":"Luminance invariant encoding in mouse primary visual cortex.","authors":"Ronan T O'Shea, Ian Nauhaus, Xue-Xin Wei, Nicholas J Priebe","doi":"10.1016/j.celrep.2024.115217","DOIUrl":"https://doi.org/10.1016/j.celrep.2024.115217","url":null,"abstract":"<p><p>The visual system adapts to maintain sensitivity and selectivity over a large range of luminance intensities. One way that the retina maintains sensitivity across night and day is by switching between rod and cone photoreceptors, which alters the receptive fields and interneuronal correlations of retinal ganglion cells (RGCs). While these adaptations allow the retina to transmit visual information to the brain across environmental conditions, the code used for that transmission varies. To determine how downstream targets encode visual scenes across light levels, we measured the effects of luminance adaptation on thalamic and cortical population activity. While changes in the retinal output are evident in the lateral geniculate nucleus (LGN), selectivity in the primary visual cortex (V1) is largely invariant to the changes in luminance. We show that the visual system could maintain sensitivity across environmental conditions without altering cortical selectivity through the convergence of parallel functional pathways from the thalamus to the cortex.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 1","pages":"115217"},"PeriodicalIF":7.5,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000775","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Neuraminidase 1 regulates neuropathogenesis by governing the cellular state of microglia via modulation of Trem2 sialylation.
IF 7.5 1区 生物学
Cell reports Pub Date : 2025-01-14 DOI: 10.1016/j.celrep.2024.115204
Leigh Ellen Fremuth, Huimin Hu, Diantha van de Vlekkert, Ida Annunziata, Jason Andrew Weesner, Alessandra d'Azzo
{"title":"Neuraminidase 1 regulates neuropathogenesis by governing the cellular state of microglia via modulation of Trem2 sialylation.","authors":"Leigh Ellen Fremuth, Huimin Hu, Diantha van de Vlekkert, Ida Annunziata, Jason Andrew Weesner, Alessandra d'Azzo","doi":"10.1016/j.celrep.2024.115204","DOIUrl":"https://doi.org/10.1016/j.celrep.2024.115204","url":null,"abstract":"<p><p>Neuraminidase 1 (NEU1) cleaves terminal sialic acids from sialoglycoproteins in endolysosomes and at the plasma membrane. As such, NEU1 regulates immune cells, primarily those of the monocytic lineage. Here, we examine how Neu1 influences microglia by modulating the sialylation of full-length Trem2 (Trem2-FL), a multifunctional receptor that regulates microglial survival, phagocytosis, and cytokine production. When Neu1 is deficient/downregulated, Trem2-FL remains sialylated, accumulates intracellularly, and is excessively cleaved into a C-terminal fragment (Trem2-CTF) and an extracellular soluble domain (sTrem2), enhancing their signaling capacities. Sialylated Trem2-FL (Sia-Trem2-FL) does not hinder Trem2-FL-DAP12-Syk complex assembly but impairs signal transduction through Syk, ultimately abolishing Trem2-dependent phagocytosis. Concurrently, Trem2-CTF-DAP12 complexes dampen NF-κB signaling, while sTrem2 propagates Akt-dependent cell survival and NFAT1-mediated production of TNF-α and CCL3. Because NEU1 and Trem2 are implicated in neurodegenerative/neuroinflammatory diseases, including Alzheimer disease and sialidosis, modulating NEU1 activity represents a therapeutic approach to broadly regulate microglia-mediated neuroinflammation.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 1","pages":"115204"},"PeriodicalIF":7.5,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000791","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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