Athanasios Kournoutis

• Kournoutis, Athanasios & Stenmark, Harald Alfred (2026). Sealing and healing: A two-step model for plasma membrane repair. Developmental Cell. ISSN 1534-5807. 61(7), s. 1345–1346. doi: 10.1016/j.devcel.2026.06.011. Fulltekst i vitenarkiv Vis sammendrag

  Plasma membrane damage can cause cell death and is associated with neurodegeneration. In this issue of Developmental Cell, Heffner et al. show that annexin A11 (ANXA11) first plugs membrane lesions, before ESCRT-III is recruited to extrude the damaged patch-a two-step repair mechanism compromised by ALS- and FTD-linked mutations.

• Odonkor, Isaac; Shrestha, Birendra Kumar; Nielsen, Stephanie Rose; Kournoutis, Athanasios; Bjørlo, Ida Emilie & Sajib, Saikat Das [Vis alle 13 forfattere av denne artikkelen] (2026). Stress-specific NONO interactomes reveal a key role of Hsp70 chaperone activity in regulation of paraspeckle formation. Journal of Cell Science. ISSN 0021-9533. 139(2). doi: 10.1242/jcs.264115. Fulltekst i vitenarkiv Vis sammendrag

  Paraspeckles are stress-induced nuclear RNA–protein condensates that assemble on the long non-coding RNA NEAT1. Their increased formation under certain cellular circumstances has gained growing interest due to their association with serious human diseases, such as neurodegenerative disorders and cancer. The biological functions of paraspeckles still appear obscure, but increasing evidence suggests that they contribute to regulation of gene expression by recruiting specific proteins and RNA molecules. Here, we have characterized and compared two stress-enriched interactomes of the essential paraspeckle protein NONO in both wild-type and paraspeckle-deficient NEAT1 knockout cells. We identified Hsp70 as part of stress-enriched NONO complexes in wild-type but not in NEAT1-depleted cells. We show that proteotoxic stress-induced paraspeckle formation and NEAT1 expression are strictly dependent on Hsp70 chaperone activity. Our data demonstrate that both NONO and Hsp70 transiently translocate to the nucleolus during heat shock and that paraspeckle formation during recovery follows Hsp70-dependent relocation of NONO from the nucleolus to the nucleoplasm. Taken together, we demonstrate an important role of Hsp70 in paraspeckle assembly and identify a possible link between the nuclear protein quality control system and paraspeckles.

• Wang, Yu; Eapen, Vinay V.; Liang, Yaosi; Kournoutis, Athanasios; Sherman, Marc Samuel & Xu, Yanxin [Vis alle 37 forfattere av denne artikkelen] (2025). WSTF nuclear autophagy regulates chronic but not acute inflammation. Nature. ISSN 0028-0836. 644(8077), s. 780–789. doi: https:/www.nature.com/articles/s41586-025-09234-1.pdf. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Abudu, Yakubu Princely; Kournoutis, Athanasios; Brenne, Hanne Britt; Lamark, Trond & Johansen, Terje (2024). MORG1 limits mTORC1 signaling by inhibiting Rag GTPases. Molecular Cell. ISSN 1097-2765. 84(3), s. 552–569.e11. doi: 10.1016/j.molcel.2023.11.023. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Kournoutis, Athanasios; Lamark, Trond; Johansen, Terje & Abudu, Yakubu Princely (2024). WDR83/MORG1 inhibits RRAG GTPase-MTORC1 signaling to facilitate basal autophagy. Autophagy. ISSN 1554-8627. doi: 10.1080/15548627.2024.2322457. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Kournoutis, Athanasios & Johansen, Terje (2023). LC3B is a cofactor for LMX1B-mediated transcription of autophagy genes in dopaminergic neurons. Journal of Cell Biology. ISSN 0021-9525. 222(5). doi: 10.1083/jcb.202303008. Fulltekst i vitenarkiv Vis sammendrag

  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, Jimenez-Moreno et al. (2023. J. Cell Biol. <a href=https://doi.org/10.1083/jcb.201910133>https://doi.org/10.1083/jcb.201910133</a>) 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.

• Rasmussen, Nikoline Lander; Kournoutis, Athanasios; Lamark, Trond & Johansen, Terje (2022). NBR1: The archetypal selective autophagy receptor. Journal of Cell Biology. ISSN 0021-9525. 221(11). doi: 10.1083/jcb.202208092. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Kournoutis, Athanasios; Gohel, Raksha; Petridi, Stavroula & Nezis, Ioannis P. (2020). Molecular mechanisms of selective autophagy in Drosophila. International Review of Cell and Molecular Biology. ISSN 1937-6448. 354, s. 63–105. doi: 10.1016/bs.ircmb.2019.08.003. Fulltekst i vitenarkiv

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• Sellæg, Kjersti; Hofsten, Susannah Beatrice von; Berge, Anne Kristin McLaren; Ligtenberg, Lennart Maximilian van; Mauseth, Marcus Moe & Kournoutis, Athanasios [Vis alle 8 forfattere av denne artikkelen] (2023). Autofagi: cellenes spareblussmodus. Fulltekst i vitenarkiv

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