生物学最新文献

Successful axonal regeneration following injury requires the effective allocation of energy. How axons withstand the initial disruption in mitochondrial energy production caused by the injury and subsequently initiate regrowth is poorly understood. Transcriptomic data showed increased expression of glycolytic genes after optic nerve crush in retinal ganglion cells with the co-deletion of Pten and Socs3. Using retinal cultures in a multicompartment microfluidic device, we observed increased regrowth and enhanced mitochondrial trafficking in the axons of Pten and Socs3 co-deleted neurons. While wild-type axons relied on mitochondrial metabolism, after injury, in the absence of Pten and Socs3, energy production was supported by local glycolysis. Specific inhibition of lactate production hindered injury survival and the initiation of regrowth while slowing down glycolysis upstream impaired regrowth initiation, axonal elongation, and energy production. Together, these observations reveal that glycolytic ATP, combined with sustained mitochondrial transport, is essential for injury-induced axonal regrowth, providing new insights into the metabolic underpinnings of axonal regeneration.

Mitochondrial reactive oxygen species (ROS) function intrinsically within cells to induce cell damage, regulate transcription, and cause genome instability. However, we know little about how mitochondrial ROS production non-cell autonomously impacts cell-cell signaling. Here, we show that mitochondrial dysfunction inhibits the plasma membrane localization of cell surface receptors that drive cell-cell communication during oogenesis. Within minutes, we found that mitochondrial ROS impairs exocyst membrane binding and leads to defective endosomal recycling. This endosomal defect impairs the trafficking of receptors, such as the Notch ligand Delta, during oogenesis. Remarkably, we found that overexpressing RAB11 restores ligand trafficking and rescues the developmental defects caused by ROS production. ROS production from adjacent cells acutely initiates a transcriptional response associated with growth and migration by suppressing Notch signaling and inducing extra cellualr matrix (ECM) remodeling. Our work reveals a conserved rapid response to ROS production that links mitochondrial dysfunction to the non-cell autonomous regulation of cell-cell signaling.

Cells maintain homeostasis via dynamic regulation of stress response pathways. Stress pathways transiently induce response regulons via negative feedback loops, but the extent to which individual genes provide feedback has not been comprehensively measured for any pathway. Here, we disrupted the induction of each gene in the Saccharomyces cerevisiae heat shock response (HSR) and quantified cell growth and HSR dynamics following heat shock. The screen revealed a core feedback loop governing the expression of the chaperone Hsp70 reinforced by an auxiliary feedback loop controlling Hsp70 subcellular localization. Mathematical modeling and live imaging demonstrated that multiple HSR targets converge to promote Hsp70 nuclear localization via its release from cytosolic condensates. Following ethanol stress, a distinct set of factors similarly converged on Hsp70, suggesting that nonredundant subsets of the HSR regulon confer feedback under different conditions. Flexible spatiotemporal feedback loops may broadly organize stress response regulons and expand their adaptive capacity.

VPS13B/COH1 is the only known causative factor for Cohen syndrome, an early-onset autosomal recessive developmental disorder with intellectual inability, developmental delay, joint hypermobility, myopia, and facial dysmorphism as common features, but the molecular basis of VPS13B/COH1 in pathogenesis remains largely unclear. Here, we identify Sec23 interacting protein (Sec23IP) at the ER exit site (ERES) as a VPS13B adaptor that recruits VPS13B to ERES-Golgi interfaces. VPS13B interacts directly with Sec23IP via the VPS13 adaptor binding domain (VAB), and the interaction promotes the association between ERES and the Golgi. Disease-associated missense mutations of VPS13B-VAB impair the interaction with Sec23IP. Knockout of VPS13B or Sec23IP blocks the formation of tubular ERGIC, an unconventional cargo carrier that expedites ER-to-Golgi transport. In addition, depletion of VPS13B or Sec23IP delays ER export of procollagen, suggesting a link between procollagen secretion and joint laxity in patients with Cohen disease. Together, our study reveals a crucial role of VPS13B-Sec23IP interaction at the ERES-Golgi interface in the pathogenesis of Cohen syndrome.

We identify BEACH domain-containing proteins (BDCPs) as novel membrane coat proteins involved in the sorting of transmembrane proteins (TMPs) on the trans-Golgi network and tubular sorting endosomes. The seven typical mammalian BDCPs share a predicted alpha-solenoid-beta propeller structure, suggesting they have a protocoatomer origin and function. We map the subcellular localization of seven BDCPs based on their dynamic colocalization with RAB and ARF small GTPases and identify five typical BDCPs on subdomains of dynamic tubular-vesicular compartments on the intersection of endocytic recycling and post-Golgi secretory pathways. We demonstrate that BDCPs interact directly with the cytosolic tails of selected TMPs and identify a subset of TMPs, whose trafficking to the plasma membrane is affected in cells lacking BDCP. We propose that the competitive binding of BDCPs and clathrin coat adaptors to the cytosolic tails of TMPs, followed by their clustering to distinct subdomains of secretory/recycling tubules function as a mechanism for sorting of TMPs in pleomorphic tubular-vesicular compartments that lack a clathrin coat.

Two recent papers by Szentgyörgyi et al. (http://doi.org/10.1083/jcb.202401167) and Pankiv et al. (http://doi.org/10.1083/jcb.202408173) provide new insights into the roles of BEACH domain proteins in membrane trafficking and cellular homeostasis. They explore which membranes they are recruited to, how they are recruited, and the potential coat-like functions of these proteins.

Technological advances in fMRI including ultra-high magnetic fields (≥ 7 T) and acquisition methods that increase spatial specificity have paved the way for studies of the human cortex at the scale of layers and columns. This mesoscopic scale promises an improved mechanistic understanding of human cortical function so far only accessible to invasive animal neurophysiology. In recent years, an increasing number of studies have applied such methods to better understand the cortical function in perception and cognition. This future perspective article asks whether closed-loop fMRI studies could equally benefit from these methods to achieve layer and columnar specificity. We outline potential applications and discuss the conceptual and concrete challenges, including data acquisition and volitional control of mesoscopic brain activity. We anticipate an important role of fMRI with mesoscopic resolution for closed-loop fMRI and neurofeedback, yielding new insights into brain function and potentially clinical applications.This article is part of the theme issue 'Neurofeedback: new territories and neurocognitive mechanisms of endogenous neuromodulation'.

Joseph Grafton Gall (1928-2024), a founder of modern cell biology, made foundational discoveries on eukaryotic chromosomes and RNA biogenesis. His major contributions include the development of in situ hybridization (later called FISH), demonstration of one DNA double helix/chromosome, isolation of the first eukaryote gene, localization of satellite DNA to centromeric heterochromatin, determination of the first telomeric DNA sequence, and elucidating the structure and functions of Cajal bodies. He was an expert microscopist, a scholar of science history, and an avid naturalist. These attributes, together with his ready embrace of new technologies, contributed to his remarkable success. He was also an early and strong supporter of women in science. His contributions to science and mentoring were recognized by numerous awards including the American Society for Cell Biology's E.B. Wilson Medal, the Society for Developmental Biology's Lifetime Achievement Award, the Albert Lasker Special Achievement Award in Medical Research, and the AAAS Mentor Award for Lifetime Achievement.

Perilipins (PLINs), the most abundant proteins on lipid droplets (LDs), display similar domain organization including amphipathic helices (AH). However, the five human PLINs bind different LDs, suggesting different modes of interaction. We established a minimal system whereby artificial LDs covered with defined polar lipids were transiently deformed to promote surface tension. Binding of purified PLIN3 and PLIN4 AH was strongly facilitated by tension but was poorly sensitive to phospholipid composition and to the presence of diacylglycerol. Accordingly, LD coverage by PLIN3 increased as phospholipid coverage decreased. In contrast, PLIN1 bound readily to LDs fully covered by phospholipids; PLIN2 showed an intermediate behavior between PLIN1 and PLIN3. In human adipocytes, PLIN3/4 were found in a soluble pool and relocated to LDs upon stimulation of fast triglyceride synthesis, whereas PLIN1 and PLIN2 localized to pre-existing LDs, consistent with the large difference in LD avidity observed in vitro. We conclude that the PLIN repertoire is adapted to handling LDs with different surface properties.

While neurofeedback represents a promising tool for neuroscience and a brain self-regulation approach to psychological rehabilitation, the field faces several problems and challenges. Current research has shown great variability and even failure among human participants in learning to self-regulate target features of brain activity with neurofeedback. A better understanding of cognitive mechanisms, psychological factors and neural substrates underlying self-regulation might help improve neurofeedback's scientific and clinical practices. This article reviews the current understanding of the neural mechanisms of brain self-regulation by drawing on findings from human and animal studies in neurofeedback, brain-computer/machine interfaces and neuroprosthetics. In this article, we look closer at the following topics: cognitive processes and psychophysiological factors affecting self-regulation, theoretical models and neural substrates underlying self-regulation, and finally, we provide an outlook on the outstanding gaps in knowledge and technical challenges. This article is part of the theme issue 'Neurofeedback: new territories and neurocognitive mechanisms of endogenous neuromodulation'.