Autophagy is crucial for T cell activation, yet how T cell receptor (TCR) signaling regulates autophagy is largely unknown. The autophagy receptor p62 was first identified as a lymphocyte-specific protein tyrosine kinase (Lck) SH2 domain ligand. However, the functional significance of the Lck-p62 association in T cells remains unclear. Here, we demonstrate that Lck inhibits TCR-induced autophagy via phosphorylating p62, thereby promoting T cell activation. Upon TCR stimulation, Lck transiently phosphorylates p62 at tyrosine 433 (Y433), peaking at 5 min and declining by 15 min. The p62-Y433F mutant displays enhanced TCR-induced association with LC3 and ULK1 complex components, thereby promoting autophagy. Consequently, this mutant suppresses TCR-induced NF-κB activation and IL-2 production by strengthening its interaction with Bcl10 and accelerating the autophagic clearance of Bcl10. Together, we demonstrate that the transient phosphorylation of p62 by Lck facilitates p62 transition between adapting Bcl10-NF-κB signaling and promoting Bcl10 autophagic degradation, revealing a temporal cooperation between TCR signaling and autophagy that occurs during the early phase of TCR stimulation. Upon T-cell receptor (TCR) stimulation, the lymphocyte-specific protein tyrosine kinase (Lck) phosphorylates p62 at Tyr433 to inhibit its autophagic receptor function, which protects Bcl10 from autophagic degradation and promotes T cell activation. Upon T-cell receptor (TCR) stimulation, the lymphocyte-specific protein tyrosine kinase (Lck) phosphorylates p62 at Tyr433 to inhibit its autophagic receptor function, which protects Bcl10 from autophagic degradation and promotes T cell activation.
RNA viruses evolve through replication errors that generate diversity but can also trigger cellular antiviral responses, creating an inherent tension between adaptation and host control. Influenza A virus biology adds to this complexity through genome segmentation, which enables reassortment but also creates infection heterogeneity through incomplete genome expression and packaging defects, and through superinfection exclusion, which restricts complementation. Together, these constraints would be expected to limit the consistent expansion of individual variants, yet the influenza A virus continues to adapt in nature, suggesting that specific infection contexts may allow disproportionate lineage amplification. To identify such contexts, we paired in vitro single-cell transcriptomics with viral lineage tracking to link infected cellular environments to viral output dynamics. We find that lineage enrichment predominantly occurs during synchronous coinfection, when multiple viral genomes occupy the same cell, and viral output is increased. These findings identify a timing-dependent condition under which lineage representation can shift, and predict that traits increasing burst output or the likelihood of synchronous coinfection may disproportionately shape population composition. Using single-cell transcriptomics and neutral viral lineage tracking, this study shows that influenza A virus lineage enrichment is preferentially associated with synchronous co-infection, when multiple viral genomes occupy the same cell, and viral output is increased. Superinfection exclusion rapidly narrows this cooperative window, making infection timing a key determinant of which viral lineages gain representation in progeny populations. Lineage enrichment predominantly occurs during synchronous co-infection, while superinfection exclusion narrows this window.
A society that threatens scientists with legal repercussions for advising the government and authorities during the COVID pandemic, not only risks losing scientific expertise needed for the next crisis but also its science and its future.
Hearing relies on the lifelong stability of the actin core within hair cell stereocilia, yet the molecular mechanisms ensuring this stability are largely unknown. Here, we identify the transcription factor Sox3 as a key regulator of this core structure in mice. In the absence of Sox3, the stereocilia core progressively disassembles, leading to hearing loss and impaired mechanotransduction. Sox3-deficient stereocilia are also more susceptible to acoustic trauma and fail to repair structural gaps, whereas Sox3 overexpression confers resilience against noise-induced damage. Mechanistically, Sox3 deletion downregulates β-thymosin genes in hair cells, most prominently Tmsb10, an essential regulator of actin monomer availability. Depleting Tmsb10 recapitulates the core degeneration observed in Sox3-deficient hair cells, establishing the Sox3-Tmsb10 axis as a novel molecular mechanism governing the lifelong preservation of the stereocilia actin core. This regulatory pathway also represents a promising target for therapeutic intervention in noise-induced hearing loss. Sox3 ablation progressively disrupts the stereocilia actin core, impairing MET function and increasing susceptibility to acoustic trauma while targeted Sox3 overexpression protects against noise-induced damage. Sox3 ablation progressively disrupts the stereocilia actin core, impairing MET function and increasing susceptibility to acoustic trauma while targeted Sox3 overexpression protects against noise-induced damage.
Axon initiation is a critical step in the establishment of neuronal morphology. However, the mechanisms regulating stable axon initiation during embryonic development remain poorly understood. Here, using fixed-tissue super-resolution and high-resolution live-tissue imaging in the developing chick spinal cord, we reveal that stable axon initiation is characterised by microtubule-directed neurofilament accumulation in the emerging axon, and identify the multifunctional G-protein Gαi2 as a regulator of this process. Before axon initiation, microtubule network orientation shifts towards the site of the future axon where coiled Gαi2-associated neurofilaments accumulate asymmetrically before unfurling into the initiating axon behind microtubules. Crucially, Gαi2 is associated with neurofilaments and microtubules at their points of contact. Gαi2 depletion reduces engagement between these cytoskeletal networks and leads to impaired passage of neurofilaments into initiating axons and disrupted axon outgrowth, supporting a role for Gαi2 in regulating microtubule-driven incorporation of neurofilaments in nascent axons. These findings advance mechanistic understanding of polarity establishment and provide insight into cytoskeletal regulation during axon formation. Live and super-resolution imaging of the developing chick spinal cord identifies a non-canonical role for Gαi2 in coupling neurofilament and microtubule networks, enabling microtubule-driven neurofilament incorporation into nascent axons that promotes persistent axon outgrowth. Live and super-resolution imaging of the developing chick spinal cord identifies a non-canonical role for Gαi2 in coupling neurofilament and microtubule networks, enabling microtubule-driven neurofilament incorporation into nascent axons that promotes persistent axon outgrowth.
