RESUMEN
The accurate construction of neural circuits requires the precise control of axon growth and guidance, which is regulated by multiple growth and guidance cues during early nervous system development. It is generally thought that the growth and guidance cues that control the major steps of axon development have been defined. Here, we describe cerebellin-1 (Cbln1) as a novel cue that controls diverse aspects of axon growth and guidance throughout the central nervous system (CNS) by experiments using mouse and chick embryos. Cbln1 has previously been shown to function in late neural development to influence synapse organization. Here, we find that Cbln1 has an essential role in early neural development. Cbln1 is expressed on the axons and growth cones of developing commissural neurons and functions in an autocrine manner to promote axon growth. Cbln1 is also expressed in intermediate target tissues and functions as an attractive guidance cue. We find that these functions of Cbln1 are mediated by neurexin-2 (Nrxn2), which functions as the Cbln1 receptor for axon growth and guidance. In addition to the developing spinal cord, we further show that Cbln1 functions in diverse parts of the CNS with major roles in cerebellar parallel fiber growth and retinal ganglion cell axon guidance. Despite the prevailing role of Cbln1 as a synaptic organizer, our study discovers a new and unexpected function for Cbln1 as a general axon growth and guidance cue throughout the nervous system.
Asunto(s)
Axones , Cerebelo , Embrión de Pollo , Animales , Ratones , Axones/metabolismo , Cerebelo/metabolismo , Médula Espinal/metabolismo , Neuronas/metabolismo , Proteínas del Tejido Nervioso/genética , Precursores de Proteínas/metabolismoRESUMEN
Autophagy is a fundamental cellular process of protein degradation and recycling that regulates immune signaling pathways via multiple mechanisms. However, it remains unclear how autophagy epigenetically regulates the immune response. Here, we identified TRIM14 as an epigenetic regulator that reduces histone H3K9 trimethylation by inhibiting the autophagic degradation of the histone demethylase KDM4D. TRIM14 recruited the deubiquitinases USP14 and BRCC3 to cleave the K63-linked ubiquitin chains of KDM4D, which prevented KDM4D from undergoing optineurin (OPTN)-mediated selective autophagy. Tripartite motif-containing 14 (TRIM14) deficiency in dendritic cells significantly impaired the expression of the KDM4D-directed proinflammatory cytokines interleukin 12 (Il12) and Il23 and protected mice from autoimmune inflammation. Taken together, these findings highlight the cross-talk between epigenetic regulation and autophagy and suggest TRIM14 is a potential target of therapeutic intervention for inflammation-related diseases.
Asunto(s)
Autofagia/fisiología , Proteínas de Ciclo Celular/metabolismo , Epigénesis Genética , Inflamación/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Histona Demetilasas con Dominio de Jumonji/metabolismo , Proteínas de Transporte de Membrana/metabolismo , Proteínas de Motivos Tripartitos/metabolismo , Animales , Autofagia/genética , Proteínas de Ciclo Celular/genética , Encefalomielitis Autoinmune Experimental/genética , Encefalomielitis Autoinmune Experimental/metabolismo , Femenino , Regulación de la Expresión Génica , Inflamación/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Histona Demetilasas con Dominio de Jumonji/genética , Proteínas de Transporte de Membrana/genética , Ratones , Ratones Noqueados , Organismos Libres de Patógenos Específicos , Proteínas de Motivos Tripartitos/genéticaRESUMEN
Viral infection triggers host innate immune responses, which primarily include the activation of type I interferon (IFN) signaling and inflammasomes. Here, we report that Zika virus (ZIKV) infection triggers NLRP3 inflammasome activation, which is further enhanced by viral non-structural protein NS1 to benefit its replication. NS1 recruits the host deubiquitinase USP8 to cleave K11-linked poly-ubiquitin chains from caspase-1 at Lys134, thus inhibiting the proteasomal degradation of caspase-1. The enhanced stabilization of caspase-1 by NS1 promotes the cleavage of cGAS, which recognizes mitochondrial DNA release and initiates type I IFN signaling during ZIKV infection. NLRP3 deficiency increases type I IFN production and strengthens host resistance to ZIKVin vitro and in vivo Taken together, our work unravels a novel antagonistic mechanism employed by ZIKV to suppress host immune response by manipulating the interplay between inflammasome and type I IFN signaling, which might guide the rational design of therapeutics in the future.
Asunto(s)
Caspasa 1/inmunología , Evasión Inmune , Nucleotidiltransferasas/inmunología , Proteolisis , Transducción de Señal/inmunología , Proteínas no Estructurales Virales/inmunología , Virus Zika/inmunología , Animales , Caspasa 1/genética , Chlorocebus aethiops , Endopeptidasas/genética , Endopeptidasas/inmunología , Complejos de Clasificación Endosomal Requeridos para el Transporte/genética , Complejos de Clasificación Endosomal Requeridos para el Transporte/inmunología , Células HEK293 , Humanos , Inflamasomas/genética , Inflamasomas/inmunología , Inflamación/genética , Inflamación/inmunología , Inflamación/patología , Inflamación/virología , Ratones , Ratones Noqueados , Nucleotidiltransferasas/genética , Transducción de Señal/genética , Células THP-1 , Ubiquitina Tiolesterasa/genética , Ubiquitina Tiolesterasa/inmunología , Células Vero , Proteínas no Estructurales Virales/genética , Virus Zika/genéticaRESUMEN
The precise control of growth and maintenance of the retinal ganglion cell (RGC) dendrite arborization is critical for normal visual functions in mammals. However, the underlying mechanisms remain elusive. Here, we find that the N6-methyladenosine (m6A) reader YTHDF2 is highly expressed in the mouse RGCs. Conditional knockout (cKO) of Ythdf2 in the retina leads to increased RGC dendrite branching, resulting in more synapses in the inner plexiform layer. Interestingly, the Ythdf2 cKO mice show improved visual acuity compared with control mice. We further demonstrate that Ythdf2 cKO in the retina protects RGCs from dendrite degeneration caused by the experimental acute glaucoma model. We identify the m6A-modified YTHDF2 target transcripts which mediate these effects. This study reveals mechanisms by which YTHDF2 restricts RGC dendrite development and maintenance. YTHDF2 and its target mRNAs might be valuable in developing new treatment approaches for glaucomatous eyes.
Asunto(s)
Glaucoma , Células Ganglionares de la Retina , Animales , Dendritas , Glaucoma/genética , Mamíferos , Ratones , Retina , SinapsisRESUMEN
N 6-methyladenosine (m6A) modification, as the most prevalent internal modification on mRNA, has been implicated in many biological processes through regulating mRNA metabolism. Given that m6A modification is highly enriched in the mammalian brain, this dynamic modification provides a crucial new layer of epitranscriptomic regulation of the nervous system. Here, in this review, we summarize the recent progress on studies of m6A modification in the mammalian nervous system ranging from neuronal development to basic and advanced brain functions. We also highlight the detailed underlying mechanisms in each process mediated by m6A writers, erasers, and readers. Besides, the involvement of dysregulated m6A modification in neurological disorders and injuries is discussed as well.
RESUMEN
Perfluoroalkyl substances (PFAS) are widely used in various manufacturing processes. Accumulation of these chemicals has adverse effects on human health, including inflammation in multiple organs, yet how PFAS are sensed by host cells, and how tissue inflammation eventually incurs, is still unclear. Here, we show that the double-stranded DNA receptor AIM2 is able to recognize perfluorooctane sulfonate (PFOS), a common form of PFAS, to trigger IL-1ß secretion and pyroptosis. Mechanistically, PFOS activates the AIM2 inflammasome in a process involving mitochondrial DNA release through the Ca2+-PKC-NF-κB/JNK-BAX/BAK axis. Accordingly, Aim2-/- mice have reduced PFOS-induced inflammation, as well as tissue damage in the lungs, livers, and kidneys in both their basic condition and in an asthmatic exacerbation model. Our results thus suggest a function of AIM2 in PFOS-mediated tissue inflammation, and identify AIM2 as a major pattern recognition receptor in response to the environmental organic pollutants.
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Ácidos Alcanesulfónicos/envenenamiento , Proteínas de Unión al ADN/metabolismo , Fluorocarburos/envenenamiento , Inmunidad Innata/efectos de los fármacos , Inflamasomas/efectos de los fármacos , Animales , Apoptosis/efectos de los fármacos , Apoptosis/genética , Asma/inducido químicamente , Asma/genética , Asma/metabolismo , Caspasa 1/metabolismo , ADN Mitocondrial/genética , ADN Mitocondrial/metabolismo , Proteínas de Unión al ADN/genética , Contaminantes Ambientales/envenenamiento , Femenino , Expresión Génica/efectos de los fármacos , Inmunidad Innata/genética , Inmunidad Innata/inmunología , Inflamasomas/genética , Inflamasomas/metabolismo , Inflamación/inducido químicamente , Inflamación/genética , Inflamación/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ratones Endogámicos C57BL , Ratones NoqueadosRESUMEN
Messenger RNA m6 A modification is shown to regulate local translation in axons. However, how the m6 A codes in axonal mRNAs are read and decoded by the m6 A reader proteins is still unknown. Here, it is found that the m6 A readers YTHDF1 and YTHDF2 are both expressed in cerebellar granule cells (GCs) and their axons. Knockdown (KD) of YTHDF1 or YTHDF2 significantly increases GC axon growth rates in vitro. By integrating anti-YTHDF1&2 RIP-Seq with the quantitative proteomic analysis or RNA-seq after KD of YTHDF1 or YTHDF2, a group of transcripts which may mediate the regulation of GC axon growth by YTHDFs is identified. Among them, Dvl1 and Wnt5a, encoding the key components of Wnt pathway, are further found to be locally translated in axons, which are controlled by YTHDF1 and YTHDF2, respectively. Specific ablation of Ythdf1 or Ythdf2 in GCs increases parallel fiber growth, promotes synapse formation in cerebellum in vivo, and improves motor coordination ability. Together, this study identifies a mechanism by which the m6 A readers YTHDF1 and YTHDF2 work synergistically on the Wnt5a pathway through regulating local translation in GC axons to control cerebellar parallel fiber development.
Asunto(s)
Axones/metabolismo , Cerebelo/metabolismo , Proteínas de Unión al ARN/metabolismo , Factores de Transcripción/metabolismo , Proteína Wnt-5a/metabolismo , Animales , Modelos Animales de Enfermedad , Ratones , Vía de Señalización WntRESUMEN
Macrophage polarization to proinflammatory M1-like or anti-inflammatory M2-like cells is critical to mount a host defense or repair tissue. The exact molecular mechanisms controlling this process are still elusive. Here, we report that ubiquitin-specific protease 19 (USP19) acts as an anti-inflammatory switch that inhibits inflammatory responses and promotes M2-like macrophage polarization. USP19 inhibited NLRP3 inflammasome activation by increasing autophagy flux and decreasing the generation of mitochondrial reactive oxygen species. In addition, USP19 inhibited the proteasomal degradation of inflammasome-independent NLRP3 by cleaving its polyubiquitin chains. USP19-stabilized NLRP3 promoted M2-like macrophage polarization by direct association with interferon regulatory factor 4, thereby preventing its p62-mediated selective autophagic degradation. Consistent with these observations, compared to wild-type mice, Usp19-/- mice had decreased M2-like macrophage polarization and increased interleukin-1ß secretion, in response to alum and chitin injections. Thus, we have uncovered an unexpected mechanism by which USP19 switches the proinflammatory function of NLRP3 into an anti-inflammatory function, and suggest that USP19 is a potential therapeutic target for inflammatory interventions.