PLoS Biology最新文献

Immunometabolism describes more than just metabolic shifts in immune cells. A new collection of articles shines a light on the many facets of immunometabolism, exploring the effects of molecular, cellular, and systemic metabolic mechanisms in health and disease.

The high prevalence of cancer immunotherapy resistance, coupled with substantial tumor heterogeneity, underscores the urgent need for innovative therapeutic targets. A deeper understanding of immunoregulatory mechanisms would provide new targets and combination therapeutic strategies for tumor therapy. In this study, we demonstrate that HSD17B12 enhances anti-tumor immunity and represents a promising therapeutic target. Mechanistically, HSD17B12 promotes lysosome-dependent degradation of PD-L1 via the VAC14 and ESCRT complexes across various malignancies, regardless of its 3-ketoacyl-CoA reductase activity. HSD17B12-deficient cells displayed PD-L1 accumulation in both tumor cells and exosomes, reducing T cell-mediated cytotoxicity. Notably, we found a significant negative correlation between HSD17B12 and PD-L1 expression in colorectal cancer tissues. Furthermore, high HSD17B12 expression in CRC correlated with increased infiltration of cytotoxic T cells. Based on these findings, we designed a peptide, HSD-CC1-NPGY, which effectively reduces PD-L1 expression in cells and suppresses tumor growth in a mouse model. Overall, our results establish HSD17B12 as an important regulator of anti-tumor immunity and a promising therapeutic target for cancer treatment.

Interferons (IFNs) are potent antiviral cytokines that are rapidly activated when infected cells sense a virus, but continued IFN production following acute infection is linked to impaired recovery. IFNs protect against infection by inducing a suite of antiviral effectors in IFN receptor-expressing cells via JAK/STAT signaling. However, how IFNs curtail tissue repair is not fully understood. Here, we studied the effects of Type III IFNs (IFNλ1 and IFNλ2) and Type I IFN (IFNβ) on tissue repair functions of human bronchial epithelial cells (HBEC). We show that both Type III IFNs and IFNβ reduce bronchial epithelial cell migration and proliferation through a common upstream mechanism: activation of LATS1, a kinase best known for limiting organ growth as part of the Hippo signaling pathway. Mechanistically, Type III IFN or IFNβ curtailed wound healing by triggering phosphorylation of LATS1 via JAK activity, bypassing activation of MST1/2, the canonical activator of LATS1 in the Hippo pathway. Further experiments showed that distinct signaling pathways lead to LATS1 and STAT1 phosphorylation downstream of IFN receptor signaling. STAT1 was dispensable for IFN-mediated LATS1 phosphorylation and suppression of tissue repair, although as expected STAT1 was required for IFN-mediated protection from rhinovirus or influenza infection. Dose-response curve experiments revealed that higher concentrations of IFN were required to trigger LATS1 phosphorylation compared to STAT1 phosphorylation. Consistently, during rhinovirus or influenza virus infection of organotypic HBEC cultures, we observed phosphorylation of both LATS1 and STAT1, but with different kinetics, with LATS1 activation showing earlier resolution compared to STAT1 activation. These results provide a conceptual framework for understanding how IFN receptor signaling differentially controls epithelial functions required for tissue repair and antiviral defense, and inform efforts to target pathological effects of IFNs following viral infection and in other high IFN states.

The clearance of mitochondria by autophagy (mitophagy) is important for cell health. Mutations in genes that are required for mitophagy, including Vps13D, PINK1, and Parkin, are associated with movement disorders, but gaps exist in our understanding of how Vps13D regulates mitophagy. Here, we identify Mtch (MTCH2 in humans) as a regulator of mitophagy based on a relationship with Vps13D during developmentally programmed mitophagy in Drosophila intestine enterocyte cells. Similar to Vps13D mutant cells, Mtch mutant cells fail to clear mitochondria and possess elevated markers of autophagy. Genetic and molecular experiments reveal that Mtch and Vps13D function in a mitophagy pathway with PINK1, Parkin, and the mitophagy receptor BNIP3. Unlike Vps13D and Parkin mutant cells, Mtch is required for proper expression of the tail-anchored protein BNIP3. Thus, the tail-anchored protein insertase function of Mtch/MTCH2 likely explains how these proteins possess multiple cell context-specific functions.

Somatic cell nuclear transfer (SCNT) is a valuable tool in regenerative medicine, yet its efficiency remains limited by epigenetic reprogramming barriers that have been partially corrected by global regulation of epigenetic enzymes. However, these approaches lack gene locus specificity and may disrupt normal gene regulation. Therefore, new strategies capable of broadly enhancing reprogramming fidelity are needed. Here, we demonstrate that overexpression of the pioneer transcription factor Nr5a2 in mouse SCNT embryos improves both zygotic genome activation and the morula-to-blastocyst transition, two major developmental barriers in SCNT, and enhances birth rates. Mechanistically, Nr5a2 recruits P300 to increase H3K27ac at genes with low expression, restoring transcriptional activity and promoting SCNT embryo development.

Land plants alternate between generations of asexual sporophytes and sexual gametophytes. Unlike seed plants, ferns produce free-living gametophytes that grow independently from their sporophytes. Gametophytes of the model fern Ceratopteris exist in two sex types: hermaphrodites and males. Hermaphrodites maintain meristems and secrete the pheromone antheridiogen, inducing undecided gametophytes to become males. In the absence of antheridiogen, males exhibit developmental plasticity and dynamic cell fate specification by initiating de novo meristems to convert into hermaphrodites. Despite its essential role, the molecular signals governing this process remain unclear. Here, we show that local auxin biosynthesis, dynamically regulated during sex-type conversion, establishes new auxin maxima that are critical for specifying and promoting the proliferation of the meristem progenitor cell (MPC) lineage, ultimately enabling the de novo formation of a multicellular meristem from a single MPC. Time-lapse imaging revealed that upon antheridiogen removal, auxin signaling is specifically activated at the initial site of proliferation in Ceratopteris males, triggering new meristem formation. This auxin signaling subsequently becomes concentrated at the center of the proliferating meristem, aligning with localized auxin biosynthesis and the emergence of the meristem notch. Computationally reconstrued lineage maps further showed that chemical inhibition of CrTAA1 abolishes these dynamic auxin patterns, blocking MPC lineage initiation and its subsequent proliferation. Furthermore, genetic knockout of CrTAA1 via CRISPR-Cas9 phenocopies the effects of chemical inhibition, preventing new meristem formation and disrupting male-to-hermaphrodite conversion. Together, these findings uncover a molecular mechanism underlying sex-type conversion in land plants and highlight the pivotal role of de novo auxin biosynthesis in orchestrating cell fate and proliferation during meristem formation.

Why the human penis is unusually large compared to that of other primates is a long-standing evolutionary question. Sexual selection, through female mate choice and male-male competition, is a likely driver, but confirming this is difficult due to natural covariation among traits. The solution is to experimentally manipulate focal traits to identify targets of selection. Using 343 computer-generated male figures that varied in penis size, height and body shape, we experimentally tested how these traits influence perceived attractiveness and fighting ability. Over 800 participants-both male and female-viewed either life-sized (in-person) or scaled (online) animations and rated the figures. Across both settings, selection analyses revealed consistent directional selection favoring taller men with a more V-shaped body and a larger penis. In both surveys, male participants rated rivals with a larger penis as more sexually competitive and physically threatening. To our knowledge, this is the first experimental evidence that males assess rivals' fighting ability and attractiveness to females based partly on a rival's penis size. Our findings suggest that female choice and male-male competition have jointly favored larger penis size, greater height, and more V-shaped bodies in men.

Skeletal muscle atrophy is a debilitating condition that significantly affects patients' quality of life and prognosis, yet its underlying mechanisms remain poorly understood. Here, we identify Optineurin (OPTN) as an active regulator for maintenance of muscle homeostasis during muscle atrophy. Knockdown (KD) of Optn induces muscle atrophy, while overexpression of Optn alleviated dexamethasone-induced muscle atrophy in mice. Mechanistically, we for the first time identified Junction plakoglobin (JUP) as a novel interacting partner of OPTN. OPTN alleviates muscle atrophy in a JUP-dependent manner, corroborating JUP as the downstream effector of OPTN-mediated muscle atrophy. RNA-seq analysis revealed that PI3K-AKT pathway is markedly downregulated in Optn-KD muscle, and pharmacological activation of PI3K-AKT pathway effectively rescued muscle atrophy in Optn-KD mice. We further show that OPTN coordinates the interaction between JUP and PI3-Kinase p85 in muscle, promoting activation of the PI3K-AKT pathway. Collectively, our study proposed a conceptual novelty that OPTN-JUP axis mediated activation of the PI3K-AKT pathway during muscle atrophy. These findings offer new insights into the mechanisms of muscle atrophy and suggest potential therapeutic strategies for this condition.

In obesity, nutrient excess and altered adipocyte secretory profiles reprogram cell-intrinsic metabolism, leading to the activation of immune cells within metabolically active tissues such as adipose tissue. This obesity-associated chronic low-grade metabolic inflammation (often referred to as metaflammation) is a well-established driver of insulin resistance and metabolic dysfunction. However, several lines of emerging evidence suggest that metaflammation is not merely a pathologic process, but may also serve as an adaptive response that supports metabolic homeostasis, particularly at the early stages of obesity. This Essay discusses immunometabolic mechanisms underlying the dual nature of metaflammation in obesity, highlighting how its initially beneficial effects can transition into detrimental outcomes.

Infantile amnesia, the inability to recall episodic memories formed during early childhood, is a hallmark of postnatal brain development. Yet the underlying mechanisms remain poorly understood. This work aimed to gain a better mechanistic understanding of infantile amnesia. Microglia, specialized macrophages of the central nervous system, are known to play an important role in synaptic refinement during postnatal development and have recently been implicated in memory-related functions. Using mouse models, we identified microglia as key regulators of memory accessibility in infancy. We profiled dynamic changes in microglial morphology across the postnatal window that paralleled the onset of infantile forgetting. We found that pharmacological inhibition of microglial activity during a specific postnatal window prevents infantile amnesia for a contextual fear memory, implicating microglia as active modulators of infant memory persistence. Using activity-dependent tagging of infant encoded engram cells, we demonstrated that microglial inhibition alters engram size and engram reactivation in the amygdala and results in changes in microglia-engram cell interactions. Furthermore, we characterized a relationship between microglial dysfunction and the lack of infantile amnesia in maternal immune activation offspring. Together, these findings reveal a novel role for microglia in regulating infant memory retrieval in mice and suggest that microglial dysfunction may contribute to altered memory trajectories in neurodevelopmental disorders.