Traffic最新文献

Import of proviral genome from the cytoplasm to the nucleus is a decisive step in the HIV-1 infection cycle, regulating which can decide the fate of HIV-1 infectivity. Exploring the heterogeneity in the replication potential of viruses emerging from various producer cells, we compared the infectivity dynamics of viruses produced by CD4+ T lymphocytes, a cell type that supports the HIV-1 propagation, with those from astrocytes that allow for limited viral replication. We found the viruses emerging from these two cell types not only differed in their infectivity, but also in the host proteins that get associated with these virions. We focused on Importin β1, an autonomous nuclear transport receptor, which was present in the virion fractions from CD4+ T lymphocytes but absent in those from astrocytes. Our analysis revealed that Importin β1 gets associated with the virus through interactions with HIV-1 Gag and Capsid proteins. Using Importin β1 knockout cell models, we found that virion-associated Importin β1 enhanced viral infectivity by facilitating the import of the viral Pre-integration complex (PIC) into the nucleus of an infected cell. Linking positive factors, such as Importin β1, to emerging virions can determine the viral infectivity in subsequent infection rounds, influencing disease progression.

Copper is one of the essential micronutrients utilized as a cofactor in a wide variety of biochemical reactions of metabolic pathways, including mitochondrial respiration and innate immune response. Cellular concentration and distribution of copper is regulated by copper-specific transporters, chaperones, metallothionein proteins and amino acids. Transcription of a major copper metallothionein, CUP1 is epigenetically regulated in Saccharomyces cerevisiae. Mutations in histones dysregulate cellular copper homeostasis due to abnormal epigenetic changes and cause diseases in humans, such as cancerous growth and neurological disorders. Low or higher cellular concentration of copper is associated with disorders such as Menkes and Wilson's disease, respectively. Higher concentrations of copper cause caspase-independent cell death known as cuproptosis and haemolytic anemia. We highlighted the existing knowledge regarding the significance of epigenetics and cellular factors in the regulation of copper metabolism and copper-regulated protein trafficking. We have also proposed a few future directions to explore the role of cellular pH dynamics, stoichiometry among metals, amino acids and protein metabolism, histone modifications, autophagy and mitochondrial respiration in regulating cellular copper metabolism. Altogether, we provide a comprehensive summary of cellular factors targeting copper metabolism for dissecting the underlying complex mechanism of copper dynamics in normal physiology and diseases.

In eukaryotes, protein secretion plays essential roles in intercellular communications and extracellular niche-building. Protein secretion generally requires a signal sequence that targets cargos to the canonical secretory pathway consisting of the endoplasmic reticulum (ER), the Golgi apparatus, plasma membrane, and vesicles moving between these compartments. However, cytoplasmic proteins lacking signal sequences (e.g., IL1β, Acb1, FGF2) have been detected, and many have defined functions in the extracellular space, suggesting unconventional protein secretion (UcPS) via alternative pathways. In recent years, scientists have uncovered many new UcPS paradigms, reporting a plethora of mechanisms that collectively form a new field. The inaugural Cold Spring Harbor Asia (CSHA) conference on "Molecular Mechanisms and Physiology of Unconventional Secretion" is the first meeting to bring these researchers together, providing a collegial platform for information sharing at this exciting frontier of cell biology research.

Small extracellular vesicles (sEVs) originate from endosomes formed during cellular endocytosis, have a diameter ranging from 30 to 150 nm and are membrane-bound prior to release, sEVs may also be formed by budding of the plasma membrane to form ectosomes. sEVs transport proteins, RNA, microRNAs (miRNAs), DNA, and other bioactive substances to facilitate information exchange and may function as mediators under physiological conditions. sEVs have various pathological roles, especially when produced by tumor parenchyma and stromal cells for signaling in the tumor-induced microenvironment. The vesicles are considered potential tumor markers and there are broad prospects for developing tumor therapies by inhibiting sEV production, secretion and uptake and eliminating circulating sEVs. sEVs may be modified to deliver chemotherapeutic drugs and this approach has shown promising results for tumor inhibition and improved prognosis. The current study reviews the role of sEVs in tumor development and explores the potential for tumor treatment.

Cervical cancer (CC) exerts a considerable impact on women's health worldwide and presents persistent challenges to conventional therapeutic strategies due to its propensity for distant metastasis, postoperative recurrence, and variable drug resistance. Ferroptosis, a recently identified type of programmed cell death, offers promising potential for a therapeutic approach for CC. This paper reviews the regulatory processes involved in ferroptosis, including the sequential events leading to cell membrane rupture via lipid peroxidation and the changes in ferroptosis sensitivity as cervical cells progress from a healthy to a malignant condition. Additionally, the dynamic relationship between ferroptosis and CC transformation driven by high-risk HPV (HR-HPV) infection is examined, with a particular focus on how HR-HPV E6/E7 proteins influence ferroptosis sensitivity. By examining the factors associated with ferroptosis, this review provides insights into CC progression and prognosis. Furthermore, therapeutic strategies targeting ferroptosis are discussed, offering novel perspectives for effective treatment options for CC.

Arf and Rab family small GTPases and their regulators, GTPase-activating proteins (GAPs) and guanine nucleotide exchange factors (GEFs), play a central role in membrane trafficking. In this study, we focused on a recently reported GAP for Arf (and potentially Rab) proteins, the CSW complex, a part of a small family of longin domain-containing proteins that form complexes with GAP activity. This family also includes folliculin and GATOR1, which are GAPs for the Rag/Gtr GTPases. All three complexes are associated with lysosomes and play a role in nutrient signaling, the latter two being directly involved in the mTOR pathway. The role of CSW is not clear, but in addition to having GAP activity on Arf proteins in vitro, its mutation causes severe neurodegenerative diseases. Here we update the reported pan-eukaryotic presence of folliculin and GATOR1, and demonstrate that CSW is also found throughout eukaryotes, though with sporadic distribution. We identify highly conserved motifs in all CSW subunits, some shared with the catalytic subunits of folliculin and GATOR1, that provide new potential avenues for experimental exploration. Remarkably, one such conserved sequence, the "GP" motif, is also found in structurally related longin proteins present in the archaeal ancestor of eukaryotes.

Recycling endosomes are essential for membrane trafficking, retrieving internalized cell surface receptors and lipids to the plasma membrane. In this study, we investigate the dynamics of tubular recycling endosomes (TREs) and their regulation. We demonstrate that TREs are highly dynamic structures that first undergo biogenesis and later fission upon internalization of CD98, a known clathrin-independent cargo. Our findings identify two new constituents and novel regulators of TRE function, CD2AP and CIN85, which are recruited to TRE through interactions with MICAL-L1 via their SH3 domains. Depletion of either CD2AP or CIN85 impairs recycling, demonstrating that these proteins play important roles in TRE function. Our study highlights the importance of coordinated protein interactions in maintaining endosomal function and identifies CD2AP and CIN85 as key regulators of the recycling pathway, potentially through their impact on the actin cytoskeleton. Understanding these mechanisms provides new insights into membrane trafficking and may have implications for diseases where endosomal recycling is disrupted.

The secretion of insulin and glucagon by pancreatic β and α cells, respectively, is critical for glucose homeostasis. While the insulin granule dynamics are well-characterized, the intracellular behavior of glucagon secretory granules (GSG) remains poorly understood. Here, we analyze the mobility of GSGs in αTC1-9 cells and insulin secretory granules (ISG) in INS-1E cells using spatiotemporal correlation spectroscopy and single-particle tracking (SPT), with a focus on the role of the cytoskeleton in regulating their transport. Under basal conditions, SPT classification reveals that GSGs predominantly exhibit diffusive motion (57.6% ± 10%), with smaller fractions categorized as almost immobile (35.8% ± 10.6%) or drifted (6.6% ± 3%), closely resembling ISG dynamics. By disrupting microtubules, we confirmed their role as active tracks for directed granule transport in both cell types. Upon exposure to their respective secretory stimuli-high glucose for β cells and low glucose for α cells-both granule populations underwent a comparable shift toward increased diffusive and drifted motions. Treatment with the actin depolymerizing agent Latrunculin-B reproduced this stimulatory effect in INS-1E cells but not in αTC1-9 cells, suggesting that despite their overall similarity in granule behavior under physiological conditions, α and β cells may rely on partially distinct mechanisms to engage the cytoskeletal network.

The mannose 6-phosphate (M6P) pathway is critical for lysosome biogenesis, facilitating the trafficking of hydrolases to lysosomes to ensure cellular degradative capacity. Fibroblast Growth Factor (FGF) signaling, a key regulator of skeletogenesis, has been linked to the autophagy-lysosomal pathway in chondrocytes, but its role in lysosome biogenesis remains poorly characterized. Here, using mass spectrometry, lysosome immune-purification, and functional assays, we reveal that RCS (Swarm rat chondrosarcoma cells) lacking FGF receptors 3 and 4 exhibit dysregulations of the M6P pathway, resulting in hypersecretion of lysosomal enzymes and impaired lysosomal function. We found that FGF receptors control the expression of M6P receptor genes in response to FGF stimulation and during cell cycle via the activation of the transcription factors TFEB and TFE3. Notably, restoring M6P pathway-either through gene expression or activation of TFEB-significantly rescues lysosomal defects in FGFR3;4-deficient RCS. These findings uncover a novel mechanism by which FGF signaling regulates lysosomal function, offering insights into the control of chondrocyte catabolism and the understanding of FGF-related human diseases.

Among extracellular vesicles (EVs), exosomes, comprised within small EVs are bilayered nanovesicles carrying specific cargo that are released into the interstitial space in a highly regulated manner. In this study, we investigated the message transmitted through macrophage-derived small EVs in response to the interaction with Trypanosoma cruzi, the protozoan responsible for Chagas disease. We utilized two distinct parasite strains, the virulent CL Brener and the attenuated TCC. When taken up by naϊve macrophages (Mφs) in vitro, small EVs derived from TCC-infected cells favor an adverse environment for parasite spread, with M1-like cytokine pattern. In contrast, EVs from CL Brener-infected cells fostered a more permissive environment with reduced TNF-α/IL-10 ratio, higher phagocytic activity and reduced migration capacity, which may hinder a timely immune response. Further, while naïve Mφs' EVs induced iNOS and nitric oxide (NO) secretion, EVs from T. cruzi-infected Mφs failed to robustly activate iNOS, suggesting the parasite may modulate EV-mediated communication to avoid NO toxicity. In vivo assays showed distinct parasitemia courses with higher parasite burden when mice were treated with small EVs from CL Brener-infected Mφs. Overall, small EVs released by infected Mφs serve as messengers in T. cruzi infection, inducing different immune responses based on parasite virulence.