Acute inflammation is an essential response that our bodies use to combat infections1. However, in the absence of infections, chronic inflammation can have a pivotal role in the onset and progression of chronic diseases, such as arthritis, cancer, autoimmune disorders, metabolic-dysfunction-associated steatohepatitis (MASH), and most ageing-associated pathologies2,3. The underlying mechanisms that distinguish chronic inflammation from its acute counterpart remain unclear, posing challenges to the development of targeted therapies for these major diseases. Here we identify a mechanism that separates the two responses: during chronic but not acute inflammation, chromatin remodelling is influenced by nuclear autophagy, in which the WSTF protein of the ISWI chromatin-remodelling complex interacts with the ATG8 autophagy protein family in the nucleus. This interaction leads to WSTF nuclear export and subsequent degradation by autophagosomes and lysosomes in the cytoplasm. Loss of WSTF leads to chromatin opening over inflammatory genes, amplifying inflammation. Cell-penetrating peptides that block the WSTF-ATG8 interaction do not affect acute inflammation but suppress chronic inflammation in senescence as well as in MASH and osteoarthritis in mouse models and patient samples. The ability to specifically target chronic inflammation without blunting acute inflammation offers an approach for treating common chronic inflammatory diseases.

Macroautophagy/autophagy is a conserved lysosomal degradation process composed of both selective and nonselective degradation pathways. The latter occurs upon nutrient depletion. Selective autophagy exerts quality control of damaged organelles and macromolecules and is going on also under nutrient-replete conditions. Proper regulation of autophagy is vital for cellular homeostasis and prevention of disease. During nutrient availability, autophagy is inhibited by the MTORC1 signaling pathway. However, selective, basal autophagy occurs continuously. How the MTORC1 pathway is fine-tuned to facilitate basal constitutive autophagy is unclear. Recently, we identified the WD-domain repeat protein WDR83/MORG1 as a negative regulator of MTORC1 signaling allowing basal, selective autophagy. WDR83 interacts with both the Ragulator and active RRAG GTPases to prevent recruitment of the MTORC1 complex to the lysosome. Consequently, WDR83 depletion leads to hyperactivation of the MTORC1 pathway and a strong decrease in basal autophagy. As a consequence of WDR83 depletion cell proliferation and migration increase and low levels of WDR83 mRNA are correlated with poor prognosis for several cancers.

Autophagy, an important quality control and recycling process vital for cellular homeostasis, is tightly regulated. The mTORC1 signaling pathway regulates autophagy under conditions of nutrient availability and scarcity. However, how mTORC1 activity is fine-tuned during nutrient availability to allow basal autophagy is unclear. Here, we report that the WD -domain repeat protein MORG1 facilitates basal constitutive autophagy by inhibiting mTORC1 signaling through Rag GTPases. Mechanistically, MORG1 interacts with active Rag GTPase complex inhibiting the Rag GTPase-mediated recruitment of mTORC1 to the lysosome. MORG1 depletion in HeLa cells increases mTORC1 activity and decreases autophagy. The autophagy receptor p62/SQSTM1 binds to MORG1, but MORG1 is not an autophagy substrate. However, p62/SQSTM1 binding to MORG1 upon re -addition of amino acids following amino acid's depletion precludes MORG1 from inhibiting the Rag GTPases, allowing mTORC1 activation. MORG1 depletion increases cell proliferation and migration. Low expression of MORG1 correlates with poor survival in several important cancers.

It is becoming increasingly clear that the Atg8 family of autophagy proteins have roles not only in the cytoplasm, but also in the cell nucleus. In this issue, Jiménez-Moreno et al. (2023. J. Cell Biol.https://doi.org/10.1083/jcb.201910133) report that nuclear LC3B binds to the LIM homeodomain transcription factor LMX1B and acts as a cofactor for LMX1B-mediated transcription of autophagy genes, providing stress protection and ensuring survival of midbrain dopaminergic neurons.

Macroautophagy (hereafter referred to as autophagy) degrades a variety of cellular components. A poorly understood area is autophagic degradation of nuclear substrates, or “nuclear autophagy”. It remains unclear what can be degraded by autophagy from the mammalian nuclei. We began our study by investigating the nuclear binding partners of ATG8 family proteins that play important roles in recognizing autophagy substrates. We systematically evaluated the ATG8 nuclear interactome in primary human cells and in mouse brain, identifying hundreds of novel interactions. We continued our study by evaluating the nuclear proteomes of cellular senescence, a stable form of cell cycle arrest program associated with inflammation, in which nuclear autophagy is involved. Combined with the ATG8 nuclear interactome data, we identified WSTF, a component of the ISWI chromatin remodeling complex, as a novel substrate of nuclear autophagy. The degradation of WSTF, mediated by a direct interaction with the GABARAP isoform of ATG8, promotes chromatin accessibility of inflammatory genes and induces senescence-associated inflammation. Furthermore, WSTF directly binds the p65 subunit of NF-κB and inhibits its acetylation, thus blocking inflammatory gene expression in the setting of senescence, cancer, and pathogen infection. In addition, we show that loss of WSTF is required for the immuno-surveillance of oncogenic Ras in mouse liver; forced expression of WSTF inhibited tumor-suppressive inflammation and led to the development of liver tumors. Taken together, our study provides a global view of mammalian nuclear autophagy and reveals a novel nuclear inhibitor of inflammation implicated in diverse pathological contexts. Targeting WSTF may be broadly valuable as therapeutic intervention of inflammatory diseases.

NBR1 was discovered as an autophagy receptor not long after the first described vertebrate autophagy receptor p62/SQSTM1. Since then, p62 has currently been mentioned in >10,000 papers on PubMed, while NBR1 is mentioned in <350 papers. Nonetheless, evolutionary analysis reveals that NBR1, and likely also selective autophagy, was present already in the last eukaryotic common ancestor (LECA), while p62 appears first in the early Metazoan lineage. Furthermore, yeast-selective autophagy receptors Atg19 and Atg34 represent NBR1 homologs. NBR1 is the main autophagy receptor in plants that do not contain p62, while most animal taxa contain both NBR1 and p62. Mechanistic studies are starting to shed light on the collaboration between mammalian NBR1 and p62 in the autophagic degradation of protein aggregates (aggrephagy). Several domains of NBR1 are involved in cargo recognition, and the list of known substrates for NBR1-mediated selective autophagy is increasing. Lastly, roles of NBR1 in human diseases such as proteinopathies and cancer are emerging.

Autophagy is a highly conserved catabolic process in which cytoplasmic material is recycled under various conditions of cellular stress, preventing cell damage and promoting survival in the event of energy or nutrient shortage, or in response to various cytotoxic insults. Autophagy is also responsible for the removal of aggregated proteins and damaged organelles, playing a vital role in the quality control of proteins and organelles. Impairment of autophagy has been linked to various diseases, including cancer and neurodegenerative disorders, making it a very interesting process for further research. Recent research highlighted that autophagy is not random and can be selective, making it even more important to understand the molecular mechanisms of selectivity at the organismal level. Drosophila has been demonstrated to be an excellent animal model for studying selective autophagy, as the autophagic machinery is highly conserved, although much is still left to be explored. In this review, an overview of autophagy and its selectivity in Drosophila will be presented.