bims-nocaut 2024-03-03 papers

Issue of 2024‒03‒03
two papers selected by
Quentin Frenger, University of Strasbourg

Autophagy. 2024 Feb 27.

Neuronal waste management: new roles for autophagy genes in the extrusion of protein aggregates and in longevity.

Ling-Hsuan Sun, Caitlin Lange, Malene Hansen, Caroline Kumsta.

A decline in macroautophagic/autophagic activity with age contributes to the accumulation of damaged molecules and is associated with the impairment of neuronal functions and the onset of age-related diseases, particularly neurodegenerative disorders. To learn about the neuronal-specific roles of autophagy genes in aging, we specifically inhibited autophagy genes pan-neuronally in C. elegans, which leads to unexpected positive impacts on neuronal homeostasis including polyQ aggregate load and organismal lifespan. These improvements are independent of canonical, degradative autophagy in neurons and instead correlated with an increase in the secretion of large, extracellular vesicles, known as exophers. We found that the ATG-16.2 WD40 domain, a conserved domain critical for at least some noncanonical autophagy functions of ATG16L1 in mammalian cells, is required for the increased exopher biogenesis, reduction in polyQ aggregate load, and lifespan extension induced by neuronal inhibition of early-acting autophagy genes. Our study suggests that noncanonical functions of ATG-16.2, and potentially other early-acting autophagy genes, may play a role in neuronal exopher formation and in C. elegans aging, extending beyond their canonical degradative functions in the autophagy process.

Keywords: ATG-16.2/ATG16L1; Aging; c. elegans; exophers; non-canonical autophagy

DOI: https://doi.org/10.1080/15548627.2024.2322420

Nat Microbiol. 2024 Feb 27.

Autophagy promotes efficient T cell responses to restrict high-dose Mycobacterium tuberculosis infection in mice.

Although autophagy sequesters Mycobacterium tuberculosis (Mtb) in in vitro cultured macrophages, loss of autophagy in macrophages in vivo does not result in susceptibility to a standard low-dose Mtb infection until late during infection, leaving open questions regarding the protective role of autophagy during Mtb infection. Here we report that loss of autophagy in lung macrophages and dendritic cells results in acute susceptibility of mice to high-dose Mtb infection, a model mimicking active tuberculosis. Rather than observing a role for autophagy in controlling Mtb replication in macrophages, we find that autophagy suppresses macrophage responses to Mtb that otherwise result in accumulation of myeloid-derived suppressor cells and subsequent defects in T cell responses. Our finding that the pathogen-plus-susceptibility gene interaction is dependent on dose has important implications both for understanding how Mtb infections in humans lead to a spectrum of outcomes and for the potential use of autophagy modulators in clinical medicine.

DOI: https://doi.org/10.1038/s41564-024-01608-x