Abstract
Autophagy selectively targets cargo for degradation, yet mechanistic understanding remains incomplete. The ATG8-family plays key roles in autophagic cargo recruitment. Here by mapping the ...proximal interactome of ATG8-paralogs, LC3B and LC3C, we uncover a LC3C-Endocytic-Associated-Pathway (LEAP) that selectively recruits plasma-membrane (PM) cargo to autophagosomes. We show that LC3C localizes to peripheral endosomes and engages proteins that traffic between PM, endosomes and autophagosomes, including the SNARE-VAMP3 and ATG9, a transmembrane protein essential for autophagy. We establish that endocytic LC3C binds cargo internalized from the PM, including the Met receptor tyrosine kinase and transferrin receptor, and is necessary for their recruitment into ATG9 vesicles targeted to sites of autophagosome initiation. Structure-function analysis identified that LC3C-endocytic localization and engagement with PM-cargo requires the extended carboxy-tail unique to LC3C, the TBK1 kinase, and TBK1-phosphosites on LC3C. These findings identify LEAP as an unexpected LC3C-dependent pathway, providing new understanding of selective coupling of PM signalling with autophagic degradation.
Urban development of watersheds increases runoff and nitrogen loads by adding urban impervious surfaces and increasing the hydrologic connectivity of these surfaces to streams. Storm water control ...measures (SCMs) are designed to disrupt this connectivity by retaining water in biologically active depressions where nitrogen retention, transformation, and removal occur. This work applies a mechanistic, spatially distributed, hydroecological model (RHESSys) to a suburban watershed in Charlotte, NC, with 15% total imperviousness (TI) and 33% watershed area mitigated by SCMs. We developed emergent relationships between watershed‐scale predictors (TI and connectivity to SCMs) and water and nitrogen response variables (storm water runoff ratios and nitrogen load by species). Results showed that annual runoff ratios were insensitive to increases in connectivity to SCMs (varying by ~1% of rainfall) because SCMs did not substantially increase evaporation but that runoff ratios increased by an average 0.2% per 1% increase in TI due to decreases in transpiration in the watershed. Generally, nitrate loads increased with TI but decreased as more surfaces were mitigated by SCMs. However, these nitrate reductions corresponded to increased export of dissolved organic nitrogen and ammonium. Together, these results indicate that SCMs act as both removers and transformers of nitrogen at the watershed scale. SCMs showed a net assimilation of nitrogen in warm months and net release in cool months, which offset the timing of nitrogen export relative to inputs. This work highlights that using a hydroecological, process‐based model reveals both the emergent relationships between watershed condition and response and the processes controlling those relationships.
Key Points
Mitigation of impervious surfaces with storm water control measures only changes annual runoff ratios by ~1%
Nitrate loads increased with total imperviousness but decreased with impervious surface connectivity to SCMs
Storm water control measures remove, retain, and transform nitrogen at the watershed scale
Urban-use pesticides are of increasing concern as they are widely used and have been linked to toxicity of aquatic organisms. To assess the occurrence and treatment of these pesticides in stormwater ...runoff, an approach combining field sampling and watershed-scale modeling was employed. Stormwater samples were collected at four locations in the lower San Diego River watershed during a storm event and analyzed for fipronil, three of its degradation products, and eight pyrethroids. All 12 compounds were detected with frequency ranging from 50 to 100%. Field results indicate pesticide pollution is ubiquitous at levels above toxicity benchmarks and that runoff may be a major pollutant source to urban surface waters. A watershed-scale stormwater model was developed, calibrated using collected data, and evaluated for pesticide storm load and concentrations under several management scenarios. Modeling results show that enhanced stormwater control measures, such as biochar-amended biofilters, reduce both pesticide storm load and toxicity benchmark exceedances, while conventional biofilters reduce the storm load but provide minimal toxicity benchmark exceedance reduction. Consequently, biochar amendment has the potential to broadly improve water quality at the watershed scale, particularly when meeting concentration-based metrics such as toxicity benchmarks. This research motivates future work to demonstrate the reliability of full-scale enhanced stormwater control measures to treat pollutants of emerging concern.
The Met/hepatocyte growth factor (HGF) receptor tyrosine kinase (RTK) is deregulated in many cancers and is a recognized target for cancer therapies. Following HGF stimulation, the signaling output ...of Met is tightly controlled by receptor internalization and sorting for degradation or recycling. Here, we uncover a role for autophagy in selective degradation of Met and regulation of Met-dependent cell migration and invasion. Met engagement with the autophagic pathway is dependent on complex formation with the mammalian ATG8 family member MAP1LC3C. LC3C deletion abrogates Met entry into the autophagy-dependent degradative pathway, allowing identification of LC3C domains required for rescue. Cancer cells with low LC3C levels show enhanced Met stability, signaling, and cell invasion. These findings provide mechanistic insight into RTK recruitment to autophagosomes and establish distinct roles for ATG8 proteins in this process, supporting that differential expression of ATG8 proteins can shape the functional consequences of autophagy in cancer development and progression.
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•Autophagy targets HGF-activated Met for degradation, decreasing Met recycling•Met interaction with MAP1LC3C is required to target Met to autophagosomes•Starvation-induced autophagy decreases Met signaling, cell motility, and invasion•In cancer, VHL loss decreases LC3C and uncouples Met from autophagic regulation
The Met RTK regulates migratory invasive responses during development and cancer. Bell et al. describe a mechanism whereby MAP1LC3C selectively targets ligand-activated Met for degradation upon starvation-induced autophagy. Loss of the VHL tumor suppressor decreases LC3C, thereby uncoupling Met from autophagic regulation and enhancing HGF-stimulated invasion in cancer.
The genomes of human herpesvirus 6A (HHV-6A) and HHV-6B have the capacity to integrate into telomeres, the essential capping structures of chromosomes that play roles in cancer and ageing. About 1% ...of people worldwide are carriers of chromosomally integrated HHV-6 (ciHHV-6), which is inherited as a genetic trait. Understanding the consequences of integration for the evolution of the viral genome, for the telomere, and for the risk of disease associated with carrier status is hampered by a lack of knowledge about ciHHV-6 genomes. Here, we report an analysis of 28 ciHHV-6 genomes and show that they are significantly divergent from the few modern nonintegrated HHV-6 strains for which complete sequences are currently available. In addition, ciHHV-6B genomes in Europeans are more closely related to each other than to ciHHV-6B genomes from China and Pakistan, suggesting regional variation of the trait. Remarkably, at least one group of European ciHHV-6B carriers has inherited the same ciHHV-6B genome, integrated in the same telomere allele, from a common ancestor estimated to have existed 24,500 ± 10,600 years ago. Despite the antiquity of some, and possibly most, germ line HHV-6 integrations, the majority of ciHHV-6B (95%) and ciHHV-6A (72%) genomes contain a full set of intact viral genes and therefore appear to have the capacity for viral gene expression and full reactivation.
Inheritance of HHV-6A or HHV-6B integrated into a telomere occurs at a low frequency in most populations studied to date, but its characteristics are poorly understood. However, stratification of ciHHV-6 carriers in modern populations due to common ancestry is an important consideration for genome-wide association studies that aim to identify disease risks for these people. Here, we present full sequence analysis of 28 ciHHV-6 genomes and show that ciHHV-6B in many carriers with European ancestry most likely originated from ancient integration events in a small number of ancestors. We propose that ancient ancestral origins for ciHHV-6A and ciHHV-6B are also likely in other populations. Moreover, despite their antiquity, all of the ciHHV-6 genomes appear to retain the capacity to express viral genes, and most are predicted to be capable of full viral reactivation. These discoveries represent potentially important considerations in immunocompromised patients, in particular in organ transplantation and in stem cell therapy.
Accurate parameterization of water quality routines within stormwater models can improve simulation, prediction of system behavior, and lead to more informed decision making. This work recognizes ...that factors controlling runoff concentrations and treatment in stormwater best management practices (BMPs) vary with region, assumes region is a proxy for these factors, and seeks to improve tool parameterization by (1) identifying a regionalization scheme that best explains variability in national datasets of runoff water quality and BMP performance, (2) generating region‐specific model parameter values, and (3) demonstrating how model output varies when using national vs. regional parameters. Of the four regionalization schemes tested, the National Climatic Data Center’s Regions best explained variance in pollutant runoff concentrations from the National Stormwater Quality Database, accounting for more data variability (1.1%) than the watershed’s land use (0.4%). For BMP performance extracted from the International Stormwater BMP Database, the United States (U.S.) Environmental Protection Agency’s Rain Zones explained the most variance (1.1%), which is one‐fifth of the variance explained by BMP type (5.0%). These results were used to generate regional parameter lookup tables for stormwater quality modeling. Test cases from the 100 most populous cites in the U.S. showed national parameters predicted BMP effluent concentrations that were 15% lower than the regional parameters for five pollutants.
Postpartum depression (PPD) affects up to 19% of women, negatively impacting maternal and infant health. Reductions in plasma oxytocin levels have been associated with PPD and heritability studies ...have established a genetic contribution. Epigenetic regulation of the oxytocin receptor gene (OXTR) has been demonstrated and we hypothesized that individual epigenetic variability at OXTR may impact the development of PPD and that such variability may be central to predicting risk. This case-control study is nested within the Avon Longitudinal Study of Parents and Children and included 269 cases with PPD and 276 controls matched on age group, parity, and presence or absence of depressive symptoms in pregnancy as assessed by the Edinburgh Postnatal Depression Scale. OXTR DNA methylation (CpG site -934) and genotype (rs53576 and rs2254298) were assayed from DNA extracted from blood collected during pregnancy. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association of elevated symptoms of PPD with genotype, methylation, and their interaction adjusted for psychosocial factors (n = 500). There was evidence of an interaction between rs53576 and methylation in the OXTR gene amongst women who did not have depression prenatally but developed PPD (p interaction = 0.026, adjusted for covariates, n = 257). Those women with GG genotype showed 2.63 greater odds of PPD for every 10% increase in methylation level (95% CI: 1.37, 5.03), whereas methylation was unrelated to PPD amongst "A" carriers (OR = 1.00, 95% CI: 0.58, 1.73). There was no such interaction among women with PPD and prenatal depression. These data indicate that epigenetic variation that decreases expression of OXTR in a susceptible genotype may play a contributory role in the etiology of PPD.
Outdoor water use represents over 50% of total water demand in semiarid and arid cities and presents both challenges to and opportunities for improved efficiency and water resilience. The current ...work adapts a remote sensing‐based methodology to estimate growing season irrigation rates at the census block group scale in Denver, Colorado. Results show that city‐wide outdoor water use does not change significantly from 1995 to 2018, while per capita water use and total water use significantly decrease from 2000 to 2018. Because total water use, but not outdoor use, is decreasing, the percent of water used outdoors significantly increases across the city from 2000 to 2018. Climate variables account for one‐quarter of interannual variation in mean irrigation rates due primarily to changes in temperature, not precipitation. Percent impervious land cover exhibits a significant inverse nonlinear relationship with irrigation rates at the census block group scale. Finally, 38% of Denver census block groups show significantly increasing irrigation rates between 1995 and 2018 driven primarily by increasing temperatures. The increasing proportion of water used for irrigation highlights the importance of outdoor demand management for urban water systems as indoor efficiencies improve. We advocate that resilient water systems necessitate integrated land use, infrastructure, and water planning in the face of urban growth and climate change. While minimizing irrigated urban areas may reduce demand, remaining green spaces should be designed to maximize multiple benefits including reductions in water demand and urban heat islands, stormwater management, and recreation to improve the sustainability of growing cities.
Key Points
The percent of water used outdoors in Denver increased from 2000 to 2018, indicating the need for improved outdoor demand management
Increasing temperatures are driving most significant increases in outdoor water use at the census block group scale in Denver
Impervious land cover is nonlinearly and inversely related to irrigation rates at the census block group level in Denver
Stormwater best management practices (BMPs) are implemented to reduce microbial pollution in runoff, but their removal efficiencies differ. Enhanced BMPs, such as those with media amendments, can ...increase removal of fecal indicator bacteria (FIB) in runoff from 0.25-log10 to above 3-log10; however, their implications for watershed-scale management are poorly understood. In this work, a computational model was developed to simulate watershed-scale bacteria loading and BMP performance using the Ballona Creek Watershed (Los Angeles County, CA) as a case study. Over 1400 scenarios with varying BMP performance, percent watershed area treated, BMP treatment volume, and infiltrative capabilities were simulated. Incremental improvement of BMP performance by 0.25-log10, while keeping other scenario variables constant, reduces annual bacterial load at the outlet by a range of 0–29%. In addition, various simulated scenarios provide the same FIB load reduction; for example, 75% load reduction is achieved by diverting runoff from either 95% of the watershed area to 25 000 infiltrating BMPs with 0.5-log10 removal or 75% of the watershed area to 75 000 infiltrating BMPs with 1.5-log10 removal. Lastly, simulated infiltrating BMPs provide greater FIB reduction than noninfiltrating BMPs at the watershed scale. Results provide new insight on the trade-offs between BMP treatment volume, performance, and distribution.
Flood frequency analysis for practical application is traditionally based on the assumption of stationarity, but this assumption has been open to doubt in recent years. A number of studies have ...focused on the nonstationary flood frequency analysis, and the associated causes of nonstationarity. In this study, the annual maximum flood peak and flood volume of Wangkuai reservoir watershed were used, and several univariate and bivariate models were established to investigate the nonstationary flood frequency, with the distribution parameters changing over the climate indices (NPO, Niño3) and the check dam indices (CDIp, CDIv). In the univariate models, the Weibull distribution performed best and exhibited an undulate behavior for both flood peak and volume, which tended to describe the nonstationarity reasonably well. The bivariate models were constructed using copulas, of which the optimal Weibull distribution in the univariate flood frequency analysis was considered as marginal distributions within the joint distribution. The results showed that the Gumbel-Hougaard copula offered the best joint distribution, and most of the probability isolines crossed each other, which demonstrated the possibility that the occurrence of combinations of the flood peak and volume may be the same under multiple effects of phase changes in the climate patterns and certain human activities (i.e. soil and water conservation). The most likely events were elaborated in diagrams, and the associated combinations of the flood peak and volume were smaller than that estimated by the fixed parameters (i.e. stationary condition) during most of the study period, while it was the opposite in 1956, 1959 and 1963. The results highlight the necessity of nonstationary flood frequency analysis under various conditions in both univariate and multivariate domains.
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