No abstract

The integral membrane protein ATG9A plays a key role in autophagy. It displays a broad intracellular distribution and is present in numerous compartments, including the plasma membrane (PM). The reasons for the distribution of ATG9A to the PM and its role at the PM are not understood. Here, we show that ATG9A organizes, in concert with IQGAP1, components of the ESCRT system and uncover cooperation between ATG9A, IQGAP1 and ESCRTs in protection from PM damage. ESCRTs and ATG9A phenocopied each other in protection against PM injury. ATG9A knockouts sensitized the PM to permeabilization by a broad spectrum of microbial and endogenous agents, including gasdermin, MLKL and the MLKL-like action of coronavirus ORF3a. Thus, ATG9A engages IQGAP1 and the ESCRT system to maintain PM integrity.

BackgroundSmoking leads to the aging of organs. However, no studies have been conducted to quantify the effect of smoking on the aging of respiratory organs and the aging-reversing ability of smoking cessation.ResultsWe collected genome-wide methylation datasets of buccal cells, airway cells, esophagus tissue, and lung tissue from non-smokers, smokers, and ex-smokers. We used the “epigenetic clock” method to quantify the epigenetic age acceleration in the four organs. The statistical analyses showed the following: (1) Smoking increased the epigenetic age of airway cells by an average of 4.9 years and lung tissue by 4.3 years. (2) After smoking ceased, the epigenetic age acceleration in airway cells (but not in lung tissue) slowed to a level that non-smokers had. (3) The epigenetic age acceleration in airway cells and lung tissue showed no gender difference.ConclusionsSmoking can accelerate the epigenetic age of human respiratory organs, but the effect varies among organs and can be reversed by smoking cessation. Our study provides a powerful incentive to reduce tobacco consumption autonomously.

We report that lysosomal damage is a hitherto unknown inducer of stress granule (SG) formation and that the process termed membrane atg8ylation coordinates SG formation with mTOR inactivation during lysosomal stress. SGs were induced by lysosome-damaging agents including SARS-CoV-2ORF3a, Mycobacterium tuberculosis, and proteopathic tau. During damage, mammalian ATG8s directly interacted with the core SG proteins NUFIP2 and G3BP1. Atg8ylation was needed for their recruitment to damaged lysosomes independently of SG condensates whereupon NUFIP2 contributed to mTOR inactivation via the Ragulator–RagA/B complex. Thus, cells employ membrane atg8ylation to control and coordinate SG and mTOR responses to lysosomal damage.

Knowing the biological age of the neonates enables us to evaluate and better understand the health and maturity comprehensively. However, because of dearth of biomarkers, it is difficult to quantify the neonatal biological age. Here we sought to quantify and assess the variability in biological age at birth and to better understand how the aging rates before birth are influenced by exposure in intrauterine period by employing a novel epigenetic biomarker of aging (epigenetic clock). We observed that the methylation age at birth was independent of the infant's sex but was significantly influenced by race. Partial correlation analysis showed a significant negative relationship between maternal socioeconomic status and infants' methylation age (r s = −0.48, P s = 0.005). A significant association with the risk of fast aging was observed for prenatal exposure to tobacco smoke with OR (95% CI) of 3.17 (1.05–9.56). Both estimated cell abundance measures and lymphocyte subpopulations in cord blood showed that tobacco exposed group exhibit an altered T cell compartment, specifically substantial loss of naive T cells. Present study provides the first evidence that common perinatal exposure (such as maternal smoking and lower socioeconomic status) may be important aging accelerators and substantial loss of naive T cells may play a role in the smoking-related fast aging phenomenon.