bims-nocaut 2024-08-04 papers

Issue of 2024–08–04
four papers selected by
Quentin Frenger, University of Strasbourg

Heliyon. 2024 Jul 15. 10(13): e33755

Immune suppressive drugs negatively regulate the CD8+T cells function by acetyltransferase p300 induced canonical and non-canonical autophagy.

Runfeng Ni, Liwei Fan, Haijin Wang, Quan Zhang, Le Zhang, Aidi Wang, Baoshan Liu.

Macroautophagy, the mainly regulated form of autophagy, maintains the cellular homeostasis and degrades the transported cargoes. It is initiated by the protein kinase complex regulating by two signals pathway Mammalian target of rapamycin complex 1 (mTORC1)-Adenosine 5' monophosphate activated protein kinase (AMPK)-Unc 51 like kinase 1(ULK1) and ULK1-PI3K- phosphatidylinositol 3-phosphate (PI3P). Currently, autolysosomes are accumulated during the aging process of CD8+T cells in vitro and may participate in inducing death sensitization of senescent cells. The main mechanism of aplastic anemia, a hyperimmune disease, is the T cells subsets imbalance such as CD8+T cells abnormal activation and hyperfunction. Therefore, the role of autophagy in the CD8+T cells and supposed whether some immunosuppress drugs induced the cells autophagic death to treat the hyperimmune diseases were focused. It was decided found that the acetyltransferase p300 obviously increased in the aplastic anemia patients and was related with the severity of disease. Previous studies have reported that canonical autophagy is regulated by the mTORC1-p300 axis. p300 is a critical bridge in the p300-VPS34 axis mediated non-canonical autophagy. There is the deficiency of autophagy and acetylation in the CD8+T cells. The expression of p300 also decreased notably after the immunosuppressive drugs therapy. Our findings provide a framework for understanding how immunosuppressive drugs effect on the AA autophagy deficiency mechanism and proved that immunosuppressive drugs negatively regulated the function of CD8+T cells by p300-mediated canonical autophagy pathway and non-canonical autophagy pathway.

Keywords: Aplastic anemia; CD8+T cells; Canonical/non-canonical autophagy; Cyclosporin A; Dioscin; mTORC1; p300

DOI: https://doi.org/10.1016/j.heliyon.2024.e33755

Mol Cell. 2024 Jul 24. pii: S1097-2765(24)00579-3. [Epub ahead of print]

The V-ATPase/ATG16L1 axis is controlled by the V1H subunit.

Lewis Timimi, Antoni G Wrobel, George N Chiduza, Sarah L Maslen, Antonio Torres-Méndez, Beatriz Montaner, Colin Davis, Taylor Minckley, Katriona L Hole, Andrea Serio, Michael J Devine, J Mark Skehel, John L Rubinstein, Anne Schreiber, Rupert Beale.

Defects in organellar acidification indicate compromised or infected compartments. Recruitment of the autophagy-related ATG16L1 complex to pathologically neutralized organelles targets ubiquitin-like ATG8 molecules to perturbed membranes. How this process is coupled to proton gradient disruption is unclear. Here, we reveal that the V1H subunit of the vacuolar ATPase (V-ATPase) proton pump binds directly to ATG16L1. The V1H/ATG16L1 interaction only occurs within fully assembled V-ATPases, allowing ATG16L1 recruitment to be coupled to increased V-ATPase assembly following organelle neutralization. Cells lacking V1H fail to target ATG8s during influenza infection or after activation of the immune receptor stimulator of interferon genes (STING). We identify a loop within V1H that mediates ATG16L1 binding. A neuronal V1H isoform lacks this loop and is associated with attenuated ATG8 targeting in response to ionophores in primary murine and human iPSC-derived neurons. Thus, V1H controls ATG16L1 recruitment following proton gradient dissipation, suggesting that the V-ATPase acts as a cell-intrinsic damage sensor.

Keywords: ATG16L1; ATP6V1H; CASM; STING; V-ATPase; VAIL; autophagy; influenza; non-canonical autophagy; vacuolar ATPase

DOI: https://doi.org/10.1016/j.molcel.2024.07.003

Cell Mol Life Sci. 2024 Jul 30. 81(1): 322

TMEM9 activates Rab9-dependent alternative autophagy through interaction with Beclin1.

Sohyeon Baek, Jae-Woong Chang, Seung-Min Yoo, JeongRim Choo, Sunmin Jung, Jihoon Nah, Yong-Keun Jung.

Transmembrane protein 9 (TMEM9) is a transmembrane protein that regulates lysosomal acidification by interacting with the v-type ATPase complex. However, the role of TMEM9 in the lysosome-dependent autophagy machinery has yet to be identified. In this study, we demonstrate that the lysosomal protein TMEM9, which is involved in vesicle acidification, regulates Rab9-dependent alternative autophagy through its interaction with Beclin1. The cytosolic domain of TMEM9 interacts with Beclin1 via its Bcl-2-binding domain. This interaction between TMEM9 and Beclin1 dissociates Bcl-2, an autophagy-inhibiting partner, from Beclin1, thereby activating LC3-independent and Rab9-dependent alternative autophagy. Late endosomal and lysosomal TMEM9 apparently colocalizes with Rab9 but not with LC3. Furthermore, we show that multiple glycosylation of TMEM9, essential for lysosomal localization, is essential for its interaction with Beclin1 and the activation of Rab9-dependent alternative autophagy. These findings reveal that TMEM9 recruits and activates the Beclin1 complex at the site of Rab9-dependent autophagosome to induce alternative autophagy.

Keywords: Alternative autophagy; Beclin1; Rab9; TMEM9

DOI: https://doi.org/10.1007/s00018-024-05366-1

Cell Mol Life Sci. 2024 Jul 30. 81(1): 323

The cellular adaptor GULP1 interacts with ATG14 to potentiate autophagy and APP processing.

Dennis Dik-Long Chau, Zhicheng Yu, Wai Wa Ray Chan, Zhai Yuqi, Raymond Chuen Chung Chang, Jacky Chi Ki Ngo, Ho Yin Edwin Chan, Kwok-Fai Lau.

Autophagy is a highly conserved catabolic mechanism by which unnecessary or dysfunctional cellular components are removed. The dysregulation of autophagy has been implicated in various neurodegenerative diseases, including Alzheimer's disease (AD). Understanding the molecular mechanism(s)/molecules that influence autophagy may provide important insights into developing therapeutic strategies against AD and other neurodegenerative disorders. Engulfment adaptor phosphotyrosine-binding domain-containing protein 1 (GULP1) is an adaptor that interacts with amyloid precursor protein (APP) to promote amyloid-β peptide production via an unidentified mechanism. Emerging evidence suggests that GULP1 has a role in autophagy. Here, we show that GULP1 is involved in autophagy through an interaction with autophagy-related 14 (ATG14), which is a regulator of autophagosome formation. GULP1 potentiated the stimulatory effect of ATG14 on autophagy by modulating class III phosphatidylinositol 3-kinase complex 1 (PI3KC3-C1) activity. The effect of GULP1 is attenuated by a GULP1 mutation (GULP1m) that disrupts the GULP1-ATG14 interaction. Conversely, PI3KC3-C1 activity is enhanced in cells expressing APP but not in those expressing an APP mutant that does not bind GULP1, which suggests a role of GULP1-APP in regulating PI3KC3-C1 activity. Notably, GULP1 facilitates the targeting of ATG14 to the endoplasmic reticulum (ER). Moreover, the levels of both ATG14 and APP are elevated in the autophagic vacuoles (AVs) of cells expressing GULP1, but not in those expressing GULP1m. APP processing is markedly enhanced in cells co-expressing GULP1 and ATG14. Hence, GULP1 alters APP processing by promoting the entry of APP into AVs. In summary, we unveil a novel role of GULP1 in enhancing the targeting of ATG14 to the ER to stimulate autophagy and, consequently, APP processing.

Keywords: Amyloid precursor protein; Autophagy-related 14; GULP1; LC3; Macroautophagy

DOI: https://doi.org/10.1007/s00018-024-05351-8