Cell reports最新文献

During fear learning, associations between a sensory cue (conditioned stimulus, CS) and an aversive stimulus (unconditioned stimulus, US) are formed in specific brain circuits. The lateral amygdala (LA) is involved in CS-US integration; however, US pathways to the LA remain understudied. Here, we investigated whether the posterior insular cortex (pInsCx), a hub for aversive state signaling, transmits US information to the LA during fear learning. We find that the pInsCx makes a robust, glutamatergic projection specifically targeting the anterior LA. In vivo Ca²⁺ imaging reveals that neurons in the pInsCx and anterior LA display US-onset and US-offset responses; imaging combined with axon silencing shows that the pInsCx selectively transmits US-offset information to the anterior LA. Optogenetic silencing, however, does not show a role for US-driven activity in the anterior LA or its pInsCx afferents in fear memory formation. Thus, we describe a cortical projection that carries US-offset information to the amygdala with a limited role in fear learning.

Hematopoietic stem and progenitor cells (HSPCs) undergo rapid transcriptional transitions among distinct cell states and functional properties during development, but the underlying molecular mechanism is largely unknown. Here, we characterize the mRNA m⁵C landscape of developing HSPCs in zebrafish and found that m⁵C modification is essential for HSPC expansion through maintaining mRNA stability. Deletion of the m⁵C reader, Y-box binding protein 1 (Ybx1), significantly inhibits the proliferation of HSPCs in zebrafish and mice. Mechanistically, Ybx1 recognizes m⁵C-modified mRNAs and maintains the stability of cell-cycle-related transcripts, thereby ensuring proper HSPC expansion. This study reveals the critical role of Ybx1-mediated mRNA m⁵C modification in developmental hematopoiesis and provides new insights and epitransciptomic strategies for optimizing HSPC expansion.

Transcriptome-wide alternative polyadenylation (APA) is involved in both innate and adaptive immune responses of immune cells. Downregulation of the CPSF6 protein, one of the 3' end-processing factors, mediates APA in macrophages with responses to virus infection and plays an important role in its anti-virus effect. However, the signaling pathway and molecular mechanism underlying the downregulation of the CPSF6 protein remain elusive. Here, we found that MAVS triggers the nuclear import of the E3 ligase SYVN1 mediated by NUP153 in response to vesicular stomatitis virus infection. Then, SYVN1 catalyzes K48-linked polyubiquitination of CPSF6, resulting in degradation of CPSF6 via the proteasome and then transcriptome-wide APA and anti-virus effects. Our results identify an antiviral mechanism via APA regulation based on ubiquitination modification of the CPSF6 protein, which may serve as a target for developing immune interventions.

Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by injury to steatotic hepatocytes that triggers the release of endogenous danger-associated molecular patterns. Recent work demonstrated that exposed lipid droplets (LDs) serve as a pathogenic signal that promotes monocyte infiltration and its maturation into triggering receptor expressed in myeloid cells 2 (TREM2⁺) macrophages in MASH liver. Here we explore the role of LD exposure in modulating inflammatory signaling in macrophages. We found that LD efferocytosis triggers a global transcriptional response and dampens pro-inflammatory signaling in macrophages. LD treatment attenuated NLRP3 inflammasome activation via mechanisms independent of lysosomal LD hydrolysis. While TREM2 was dispensable for LD efferocytosis by macrophages, it was required for the attenuation of proinflammatory signaling upon LD exposure. Additionally, MS4A7 downregulation contributes to LD efferocytosis-mediated dampening of inflammatory response. These results underscore the dual role of LD exposure in MASH liver by promoting monocyte infiltration and TREM2⁺ macrophage induction, while restraining proinflammatory response in macrophages.

We recently demonstrated that vaccines comprising antigenic peptides conjugated to a glycolipid agonist, termed glycolipid-peptide (GLP) vaccines, efficiently generate substantial numbers of long-lived CD8⁺ liver-resident memory T (Trm) cells that are crucial for protection against malaria liver-stage infection. To understand the underlying mechanism, we examined the prerequisites for priming, differentiation, and secondary boosting of liver Trm cells using these GLP vaccines. Our study revealed that generation of long-lived liver Trm cells relies on CD8⁺ T cell priming by type 1 conventional dendritic (cDC1) cells, followed by post-priming exposure to a combination of vaccine-derived inflammatory and antigenic signals. Boosting of liver Trm cells is feasible using the same GLP vaccine, but a substantial delay is required for optimal responses due to natural killer T (NKT) cell anergy. Overall, our study unveils key requirements for the development of long-lived liver Trm cells, offering valuable insights for future vaccine design.

The endoplasmic reticulum (ER) stress response controls the balance between cellular survival and death. Here, we implicate SCOTIN, an interferon-inducible ER protein, in activating the ER stress response and modulating cell fate through its proline-rich domain (PRD)-mediated cytosolic condensation. SCOTIN overexpression leads to the formation of condensates enveloping multiple layers of the ER, accompanied by morphological signs of organelle stress. Luminal BiP chaperone proteins are sequestered within these SCOTIN condensates, which elicit ER stress responses. The colocalization of luminal BiP with SCOTIN is strictly contingent upon the PRD-mediated condensation of SCOTIN in the cytosolic compartment, closely associated with the ER membrane. The cysteine-rich domain (CRD) of SCOTIN, along with the condensation-prone PRD domain, is required for ER stress induction. We propose that membrane-associated condensation transduces signals across the ER membrane, leading to the induction of BiP assembly and the ER stress response.

Orexin/hypocretin receptor type 2 (Ox2R), which is widely expressed in the brain, receives orexin signals and modulates sleep and metabolism. Ox2R selective agonists are currently under clinical trials for narcolepsy treatment. Here, we focused on Ox2R expression and function in melanin-concentrating hormone (MCH) neurons, which have opposite roles to orexin neurons in sleep and metabolism regulation. Ox2R-expressing MCH neurons showed heterogeneity of RNA expression, and orexin B application in brain slices induced both excitatory and inhibitory responses in distinct MCH neuron populations. Ox2R inactivation in MCH neurons reduced transitions from non-rapid eye movement (NREM) to REM sleep and impaired insulin sensitivity with excessive feeding after a fasting period in female mice. In conclusion, Ox2R mediates excitatory and inhibitory responses in MCH neuron sub-populations in vivo, which regulate sleep and metabolism in female mice.

The dorso-lateral prefrontal cortex (dlPFC) contributes to flexible, goal-directed behaviors. However, a coherent picture of dlPFC function is lacking, as its activity is often studied only in relation to a few events within a fully learned behavioral task. Here we obtain a comprehensive description of dlPFC activity across different task epochs, saccade types, tasks, and learning stages. We consistently observe the strongest modulation of neural activity in relation to a retrospective representation of the most recent saccade. Prospective, planning-like activity is limited to task-related, delayed saccades directly eligible for a reward. The link between prospective and retrospective representations is highly structured, potentially reflecting a hard-wired feature of saccade responses. Only prospective representations are modulated by the recent behavioral history, but neither representation is modulated by day-to-day behavioral improvements. The dlPFC thus combines tightly linked flexible and rigid representations with a dominant contribution from retrospective signals maintaining the memory of past actions.

Activated proinflammatory T helper (Th) cells, including Th1 and Th17 cells, drive immune responses against pathogens and contribute to autoimmune diseases. We show that the expression of inositol polyphosphate multikinase (IPMK), an enzyme essential for inositol phosphate metabolism, is highly induced in Th1 and Th17 subsets. Deletion of IPMK in CD4⁺ T cells leads to diminished Th1- and Th17-mediated responses, reducing resistance to Leishmania major and attenuating experimental autoimmune encephalomyelitis. IPMK-deficient CD4⁺ T cells show impaired activation and Th17 differentiation, linked to the decreased activation of Akt, mTOR, and STAT3. Mechanistically, IPMK functions as a phosphatidylinositol 3-kinase to regulate phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)P₃) production, promoting T cell activation and effector functions. In IPMK-deficient CD4⁺ T cells, T cell receptor-stimulated PtdIns(3,4,5)P₃ generation is abolished by wortmannin, suggesting IPMK acts in a wortmannin-sensitive manner. These findings establish IPMK as a critical regulator of Th1 and Th17 differentiation, underscoring its role in maintaining immune homeostasis.