Understanding the relationship between viral proteins and host factors is essential for developing strategies to control virus infections. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects host cells using angiotensin converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2) as viral receptor and priming protease during the viral entry phase. Here, we report that TMPRSS2 reduces the infectivity of SARS-CoV-2 and HIV-1 during the viral production phase. Treatment of virus-producing cells with a TMPRSS2 inhibitor increases the production of infectious virions. TMPRSS2 enzymatic activity specifically disrupts the trans-Golgi by phosphorylating Golgi stacking proteins through ERK activation, which disturbs virion spike incorporation and structural maturation of the viral envelope glycoproteins, causing lower viral infectivity. We find that SARS-CoV-2 envelope protein (E protein) counteracts this TMPRSS2 activity to rescue SARS-CoV-2-S incorporation. These results demonstrate negative regulation of viral envelope glycoprotein incorporation by TMPRSS2 and reveal that SARS-CoV-2 regulates the Golgi system to create an optimal viral replication environment.

While much is known about the effects of the chemical microenvironment on cellular metabolism, mechanical cues have emerged as critical stimuli of intracellular metabolic pathways. Mechanical signals from the extracellular matrix (ECM), neighboring cells, and the microenvironment intersect with key regulators of cellular metabolism, often leading to changes in fundamental cell behaviors, including cell proliferation and migration. Here, we review recent work that has uncovered a role for mechanical cues from microenvironmental factors on cellular metabolism. We discuss how cell-ECM interactions and forces such as shear, tension, and compression affect cellular metabolic requirements and energy production. Importantly, mechanometabolism shapes both physiological homeostasis and pathological states, and further investigation has implications for understanding tissue function and disease progression and uncovering potential therapeutic strategies.

Defence systems against genetic mobile elements are highly adaptable, yet their long-term evolutionary stability remains unclear. To address this, we examined the conservation of Piwi-interacting RNA (piRNA)-mediated defence against envelope-carrying gypsy long terminal repeat (LTR) retrotransposons across insects beyond Drosophila. We show that Aedes aegypti (yellow fever mosquito) and Anopheles stephensi (Asian malaria mosquito), as well as Tetragonula carbonaria (stingless bees), Acheta domesticus (house cricket) and Teleogryllus oceanicus (Pacific field cricket), all produce piRNAs targeting gypsy elements in ovarian somatic cells-the same cellular niche where Drosophila mounts piRNA defence against gypsy-indicating a persistent arms race for more than 400 million years of insect evolution. Notably, in Aedes aegypti, ovarian somatic cells express the same piRNA clusters as other somatic tissues, where they are known to target RNA viruses-suggesting a shared origin of anti-viral and anti-retrotransposon defences. Furthermore, we observe lineage-specific differences in ovarian somatic piRNA biogenesis: slicing-independent phasing appears to dominate in dipterans, ping-pong amplification in bees, and slicing-dependent phasing in crickets. Together, these findings indicate that distinct piRNA pathways have independently evolved at different timepoints to silence the same class of retrotransposons in insect evolution.

Cells decode mechanical cues to direct fate decisions through nuclear remodeling, yet nuclear adaptors to mechanical signals remain elusive. Here, we show that soft matrix suppresses myoblast differentiation and induces nuclear abnormality within 30 min, accompanied by a greater than 60% reduction in lamin B1 proteins levels. Mechanistically, midnolin interacts with lamin B1 and mediates ubiquitination-independent degradation of lamin B1 on soft matrix, through the Catch domain of midnolin engaging a β-strand within lamin B1's Ig-like domain. Functionally, moderate lamin B1 expression is essential for myoblast differentiation initiation, as its depletion either by siRNA or CRISPR knockout abolishes myogenic capacity. Our findings reveal that the midnolin-proteasome axis directly converts mechanical inputs into lineage commitment by triggering lamin B1 degradation, defining a novel nuclear mechano-adaptation pathway.

Notch signaling is an evolutionarily conserved pathway known to orchestrate neurogenesis by regulating the transition from progenitors to neurons and glia, and by directing neurite outgrowth and axon guidance in many species. Although extensively studied in vertebrates and ecdysozoans, the role of Notch in spiralians remains unexplored, limiting our understanding of its conserved functions across bilaterians. Here we focus on the segmented annelid Platynereis dumerilii, a model organism in neurobiology and regeneration, to investigate Notch signaling functions during post-embryonic developmental processes. We show that Notch pathway components are expressed in neurogenic territories during both posterior elongation and regeneration, two processes requiring sustained neurogenesis. Through chemical inhibitions of the pathway and RNA-seq profiling, we find that Notch signaling regulates neural progenitor specification, differentiation, and overall neurogenic balance in the regenerating and elongating posterior part. Disruption of Notch signaling activity leads to severe defects in pygidial and central nervous system organization. Altogether, our results support the hypothesis that Notch has multifaceted conserved functions in neurogenesis across bilaterians, shedding light on the ancestral functions of this critical pathway.

Neural progenitor cell (NPC) proliferation is fundamental for population expansion and brain development. G1 phase control determines the cell cycle duration of NPCs and thereby affects their proliferation efficiency. However, the molecular mechanisms governing G1 phase progression in NPCs remain unclear. Here, we show that AKT gain-of-function mutations and pharmacological inhibition exert opposing effects on NPC proliferation. Consistently, Emx1-Cre-mediated deletion of Akt1/2/3 in mice impairs NPC proliferation and disrupts cortical development. We find that AKT deficiency induces G1 phase arrest and prolongs the cell cycle of NPCs. Mechanistically, we demonstrate that AKT-mediated phosphorylation inhibits the activity of CRL4AMBRA1 E3 ubiquitin ligase to safeguard cyclin D2 (CCND2) stability. Specifically, AKT phosphorylates DDB1, the adaptor of CRL4AMBRA1, which disrupts its interaction with CCND2 and reduces its degradation. These findings reveal a post-translational mechanism impacting NPC cell cycle and cortical morphogenesis, providing insight into the etiology of malformations of cortical development.

Cytomegaloviruses are highly adapted to their hosts through millions of years of co-evolution. Most human (H)CMV infections occur early in life when the virus enters via the mucosal surfaces of the respiratory or gastrointestinal tract. These infections are usually asymptomatic, but coincide with critical phases of immune development, shaping long-term host immunity. In rare but clinically significant cases, CMV can invade protected sites, such as the central nervous system, leading to symptomatic disease. As the most abundant immune cells at barrier sites, myeloid cells support all stages of the viral life cycle: replication, dissemination, and latency. During the perinatal period, the myeloid compartment undergoes profound changes, including macrophage maturation, monocyte influx, and functional adaptation. CMV may exploit these developmental transitions to establish infection and to cross tissue barriers. This review discusses how CMV manipulates myeloid immune cells to establish postnatal infection, particularly via the respiratory tract, and explores strategies by which CMVs breach the placental barrier and access the fetal brain. The review integrates evidence from multiple CMV species, with emphasis on human and mouse data.

While both common and rare variants contribute to the genetic etiology of complex traits, whether their impacts manifest through the same effector genes and molecular mechanisms is not well understood. Here, we systematically analyze common and rare variants associated with each of 373 phenotypic traits within a large biological knowledge network of gene and protein interactions. While common and rare variants implicate few shared genes, they converge on shared molecular networks for more than 75% of traits. We demonstrate that the strength of this convergence is influenced by core factors such as trait heritability, gene selective constraint, and tissue specificity. Using neuropsychiatric traits as examples, we show that common and rare variants impact genes with shared functions across multiple levels of biological organization. These findings underscore the importance of integrating variants across the frequency spectrum and establish a foundation for network-based investigations of the genetics of diverse human diseases and phenotypes.

Microtubules perform a variety of cellular functions, including regulation of mitotic cell division, cilia formation, and neurite extension. Post-translational modifications controlled by the TTLL-family of enzymes confer a host of properties that affect microtubule dynamics and function. Specifically, polyglutamylation of tubulin C-terminal tails plays an important role in regulating microtubule dynamics and function within specific cellular contexts. In this study, we examined contributions from and potential regulators of polyglutamylation during mitosis, focusing on the microtubule remodeling that occurs in telophase once the mitotic spindle has completed chromosome separation. We demonstrate that the anaphase-to-telophase transition is accompanied by an increase in short-chain polyglutamylation of central spindle microtubules. We also show that TTLL1 and TPGS1, subunits of the tubulin polyglutamylation complex, are targeted to the intracellular bridge and midbody during cell progression through telophase. Finally, we demonstrate that loss of TPGS1 leads to defects in remodeling of the central spindle during telophase and impacts the cell's ability to complete mitotic cell division.

The social behaviors of microbes provide unique opportunities for testing social evolution theories. How can altruistic behaviors arise by natural selection is a central challenge in biology. Green-beard effect has been proposed as a basic mechanism for the evolution of altruistic behaviors. Yet, green-beard genes are generally thought to be rare. Here, we find that the Schizosaccharomyces pombe gsf2 gene mediates flocculation-like aggregation, and flocculation is triggered by acid stresses. gsf2-expressing cells preferentially adhere to each other. The expression of gsf2 is costly, but gsf2-expressing cells preferentially adhere to each other and protect each other from external stress. Gsf2 is highly variable in natural populations, likely contributing to different flocculation intensity. These findings suggest that gsf2 is a gradient green-beard gene that drives the altruism among gsf2 carriers. Moreover, we find that gsf2 is a new gene that originated very recently. Our results provide insights into the origin and evolution of green-beard genes.