Cell reports最新文献

Itch serves as a self-protection mechanism against harmful external agents, whereas uncontrolled and persistent itch severely influences the quality of life of patients and aggravates their diseases. Unfortunately, the existing treatments are largely ineffective. The current difficulty in treatment may be closely related to the fact that the central neural mechanisms underlying itch processing, especially descending inhibition of itch, are poorly understood. Here, we demonstrate that an excitatory descending neural circuit from rostral anterior cingulate cortex pyramidal (rACC^Py) neurons to periaqueductal gray GABAergic (PAG^GABA) neurons plays a key role in the inhibition of itch. The activity of itch-tagged rACC^Py neurons decreases during the itch-evoked scratching period. Artificial activation or inhibition of the neural circuits significantly impairs or enhances itch processing, respectively. Thus, an excitatory neural circuit is identified as playing a crucial inhibitory role in descending regulation of itch, suggesting that it could be a potential target for treating itch.

Plant roots grow in association with a community of microorganisms collectively known as the rhizosphere microbiome. Immune activation in response to elicitors like the flagellin-derived epitope flg22 restricts bacteria on plant roots but also inhibits plant growth. Some commensal root-associated bacteria are capable of suppressing the plant immune response to elicitors. In this study, we investigated the ability of 165 root-associated bacteria to suppress flg22-induced immune activation and growth restriction. We demonstrate that a type II secreted subtilase, which we term immunosuppressive subtilase A (IssA), from Dyella japonica strain MF79 cleaves the immune elicitor peptide flg22 and suppresses immune activation. IssA homologs are found in other plant-associated commensals, with particularly high conservation in the order Xanthomonadales. This represents a novel mechanism by which commensal microbes modulate flg22-induced immunity in the rhizosphere microbiome.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder characterized by extracellular amyloid plaques and neuronal Tau tangles. A recent study found that the APOE3 Christchurch (APOECh) variant could delay AD progression. However, the underlying mechanisms remain unclear. In this study, we established neuron-microglia co-cultures and neuroimmune organoids using isogenic APOE3 and APOECh microglia derived from human induced pluripotent stem cells (hiPSCs) with PSEN1 mutant neurons or brain organoids. We show that APOECh microglia are resistant to Aβ-induced lipid peroxidation and ferroptosis and therefore preserve the phagocytic activity and promote pTau clearance, providing mechanistic insights into the neuroprotective role of APOE3Ch microglia. Moreover, we show that an APOE mimetic peptide can mimic the protective effects of APOECh microglia. These findings demonstrate that the APOECh microglia plays a causal role in microglial neuroprotection, which can be exploited for therapeutic development for AD.

During clathrin-mediated endocytosis (CME), dozens of proteins are recruited to nascent CME sites on the plasma membrane, and their spatial and temporal coordination is crucial for efficient CME. Here, we show that the scaffold protein intersectin1 (ITSN1) promotes CME by organizing and stabilizing endocytic protein interaction networks. Live-cell imaging of genome-edited cells revealed that endogenously labeled ITSN1 is recruited during CME site stabilization and growth and that ITSN1 knockdown impairs endocytic protein recruitment during this stage. Targeting ITSN1 to the mitochondrial surface was sufficient to assemble puncta consisting of the EPS15 and FCHO2 initiation proteins, the AP2 and epsin1 (EPN1) adaptor proteins, and the dynamin2 (DNM2) vesicle scission GTPase. ITSN1 can form puncta and recruit DNM2 independent of EPS15/FCHO2 or EPN1. Our findings redefine ITSN1's primary endocytic role as organizing and stabilizing CME protein interaction networks rather than initiation, providing deeper insights into the multi-step and multi-zone organization of CME site assembly.

Sorafenib, the targeted therapy for hepatocellular carcinoma (HCC), has been utilized in clinics for over a decade. However, its effectiveness is severely hindered by acquired drug resistance, the mechanisms of which remain largely elusive. In this study, we identify that carbonic anhydrase 2 (CA2) is a key regulator of sorafenib resistance. Mechanistically, sorafenib treatment decreases intracellular pH (pH_i) by suppressing monocarboxylate transporter 4 (MCT4) expression, while high levels of CA2 counteract MCT4-mediated pH_i dysregulation upon sorafenib treatment, maintaining pH_i homeostasis to facilitate cell survival and sorafenib resistance. Targeting CA2 re-sensitizes resistant HCC cells to sorafenib both in vitro and in vivo. Importantly, analysis of clinical samples shows a strong correlation between CA2 expression levels and the therapeutic efficacy of sorafenib in HCC patients. Our findings highlight the significance of CA2 in facilitating sorafenib resistance and propose targeting CA2 as a potential strategy for overcoming sorafenib resistance in HCC patients.

Macroautophagy (autophagy) involves the formation of phagophores that mature into autophagosomes. The impact of inhibiting autophagosome closure remains unclear. Here, we report the generation and analysis of mice with impaired autophagosome closure by targeting the ubiquitin E2 variant-like (UEVL) β strands of the endosomal sorting complex required for transport (ESCRT) I subunit VPS37A. The VPS37A UEVL mutation (Δ43-139) impairs bulk autophagic flux without disrupting ESCRT-I complex assembly and endosomal function. Homozygous mutant mice exhibit signs of autophagy impairment, including p62/SQSTM1 and ubiquitinated protein accumulation, neuronal dysfunction, growth retardation, antioxidant gene upregulation, and tissue abnormalities. However, about half of the mutant neonates survive to adulthood without severe liver injury. LC3 proximity proteomics reveals that the VPS37A UEVL mutation leads to active TANK-binding kinase 1 (TBK1) accumulation on phagophores, resulting in increased p62 phosphorylation and inclusion formation. These findings reveal a previously unappreciated role of LC3-conjugated phagophores in facilitating protein aggregation and sequestration, potentially alleviating proteotoxicity.

PD-1 blockade enhances anti-tumoral CD8⁺ T cell responses via type 1 conventional dendritic cells (cDC1s), but how cDC1s change the properties of intratumoral CD8⁺ T cells remains to be determined. Here, we identified two populations of intratumoral CD8⁺ T cells distinguished by their expression of asialo-ganglio-N-tetraosylceramide (asGM1). asGM1^neg and asGM1^posCD8⁺ T cells show enriched expression of genes characteristic for precursor exhausted T (Tpex) cells and terminally exhausted T (Tex) cells, respectively. The in situ expression of Flt3L or inhibition of PD-1 each promote the differentiation of asGM1^negCD8⁺ T cells into asGM1^posCD8⁺ T cells via interleukin-12 (IL-12) while also increasing the expression of Tpex and effector-like T cell-associated genes and their effector functions. Both interventions selectively expand CD8⁺ T cells, but only Flt3L expression broadens their T cell receptor (TCR) repertoire. These data indicate the distinct role of Flt3L in diversifying the TCR repertoire, offering potential solutions for immune checkpoint blockade-resistant cancers.

Piwi-interacting RNAs (piRNAs) are the main repressors of transposable elements (TEs) in animal germlines. In Drosophila, Piwi-piRNA complexes associate with nascent TE transcripts to drive heterochromatin formation and TE repression. However, previous studies have shown that Piwi also associates with large numbers of mRNAs, raising the question of how Piwi discriminates between mRNAs and TEs. To answer this question, we performed a comprehensive analysis of Piwi-associated RNAs, compositionally and functionally, to decipher the targeting rules of Piwi-piRNA complexes. While Piwi initially identifies its targets through the seed sequence, it requires pairing well beyond the seed, nearly a perfect match, to elicit a repressive response. In addition to the complementarity of piRNAs to their targets, their abundance must reach a certain threshold to be functional. Together, these findings explain large differences in the target repression of Piwi-associated RNAs and reveal how Piwi efficiently distinguishes TEs from mRNAs despite associating with both.

SLC25A3 encodes mitochondrial phosphate carrier (PiC), which is involved in inorganic phosphate transport. Clinical reports have found that most patients with homozygous or complex heterozygous mutations in SLC25A3 exhibit lactic acidosis, cardiac hypertrophy, and premature death. However, the potential molecular mechanisms underlying these associations remain unclear. Using CRISPR-Cas9 technology, we generated human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) carrying SLC25A3-knockout (KO) or missense mutations (c.C544T, c.A547G, c.C349T) to elucidate the pathogenic mechanisms of SLC25A3-related hypertrophic cardiomyopathy (HCM) and evaluate potential therapeutic interventions. These SLC25A3-KO or missense mutation hiPSC-CMs recapitulated the disease phenotype associated with myocardial hypertrophy, including diastolic dysfunction, Ca²⁺ homeostasis imbalance, and mitochondrial energy metabolism dysfunction. Further studies suggested the potential link between the accumulation of glycolytic byproducts and Ca²⁺ homeostasis imbalance in SLC25A3-KO hiPSC-CMs. Finally, we explored the prospective therapeutic implications of mitochondrial transplantation in rescuing SLC25A3-related HCM.

Lipid droplets (LDs) are dynamic organelles essential for lipid storage and organismal survival. Studies have highlighted the importance of glial function in brain LD formation during aging; however, the genes and mechanisms involved remain elusive. Here, we found that Ugt35b, a member of the uridine diphosphate (UDP)-glycosyltransferases that catalyze the transfer of glycosyl groups to acceptors, is highly expressed in glia and crucial for Drosophila lifespan. By integrating multiomics data, we demonstrated that glial Ugt35b plays key roles in regulating glycerolipid and glycerophospholipid metabolism in the brain. Notably, we found that Ugt35b and Lsd-2 are co-expressed in glia and confirmed their protein interaction in vivo. Knockdown of Ugt35b significantly reduced LD formation by downregulating Lsd-2 expression, while overexpression of Lsd-2 partially rescued the shortened lifespan in glial Ugt35b RNAi flies. Our findings reveal the crucial role of glial Ugt35b in regulating LD formation to maintain brain lipid homeostasis and support Drosophila lifespan.