bims-nocaut 2024-10-20 papers

Issue of 2024–10–20
four papers selected by
Quentin Frenger, University of Strasbourg

Autophagy. 2024 Oct 16. 1-2

AKT2-mediated lysosomal dysfunction promotes secretory autophagy in retinal pigment epithelium (RPE) cells.

Sayan Ghosh, Stacey Hose, Debasish Sinha.

Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with the non-neovascular or atrophic form being the most common. Current treatment options are limited, emphasizing the urgent need for new therapeutic strategies. Our key finding is that increased levels of AKT2 in the RPE cells impair lysosomal function and trigger secretory autophagy; a non-canonical macroautophagy/autophagy pathway where cellular materials are released via the plasma membrane rather than being degraded by lysosomes. We showed that this process involves a protein complex, AKT2-SYTL1-TRIM16-SNAP23, releasing factors contributing to drusen biogenesis, a clinical hallmark of AMD development. Importantly, SIRT5 can inhibit this pathway, potentially offering a protective effect. Understanding mechanisms by which this non-canonical autophagy pathway promotes extracellular waste accumulation could provide new insights into drusen biogenesis. Future therapies for atrophic AMD could focus on regulating secretory autophagy or manipulating proteins involved in this process.

Keywords: Atrophic age-related macular degeneration; drusen; inflammation; lysosomes; retinal pigment epithelium cells; secretory autophagy

DOI: https://doi.org/10.1080/15548627.2024.2413305

Int J Biol Macromol. 2024 Oct 12. pii: S0141-8130(24)07329-X. [Epub ahead of print] 136520

"β-glucan signalling stimulates NOX-2 dependent autophagy and LC-3 associated autophagy (LAP) pathway".

Firoz Ahmad, Shad Ahmad, Anurag Kumar Srivastav, Tarun Kumar Upadhyay, Adil Husain, Mohd Khubaib, Sojin Kang, Moon Nyeo Park, Bonglee Kim, Rolee Sharma.

β-Glucans, a complex polysaccharide derived from fungal and yeast cell walls, play a crucial role in modulating immune responses through their interaction with receptors such as Dectin-1 and Complement receptor 3 (CR-3). This review provides an in-depth analysis of the molecular mechanisms by which β-glucans activate receptor-mediated signalling pathways, focusing particularly on the LC3-associated phagocytosis (LAP) and autophagy pathways. Hence, we explore how β-glucan receptor engagement stimulates NADPH oxidase 2 (NOX-2), leading to the intracellular production of significant level of reactive oxygen species (ROS) essential for both conventional autophagy and LAP. While significant progress has been made, but the regulation of phago-lysosomal maturation and antigen presentation during LAP induction still remains less explored. This review main aims were to provide a comprehensive overview of these pathways and their regulation by β-glucans. By consolidating current knowledge, we seek to highlight how these mechanisms can be leveraged for therapeutic applications, particularly in the context of tuberculosis (TB) management, where β-glucans could serve as host-directed adjuvant therapies to combat drug-resistant strains. Despite major advancements in this field, currently key research gaps still persist, including detailed molecular interactions between β-glucan receptors and NOX-2 and the translation of these findings to in vivo models and clinical investigations. This review underscores the need for further research to explore the therapeutic potential of β-glucans in managing not only tuberculosis but also other diseases such as cancer, cardiovascular conditions, and metabolic disorders.

Keywords: Autophagy; Dectin-1; NOX-2; PAMPs; Toll like receptors; β-Glucan

DOI: https://doi.org/10.1016/j.ijbiomac.2024.136520

Autophagy. 2024 Oct 13.

CLC2 (clathrin light chain 2)-ATG8h/ATG8i interactions connect clathrin-mediated endocytosis (CME) and the autophagy pathway.

Hujiao Lan, Yating Zhao, Minjun Huang, Wenxu Wang, Jianzhong Liu.

Extensive interconnection has been established between clathrin-mediated endocytosis (CME) and the macroautophagy/autophagy pathway in yeast and mammals. However, the evidence that connects these two pathways in plants has been limited. Starting from the phenotypic similarities in carbon starvation and immune responses shared between the double mutant of CLC2 (clathrin light chain 2) and CLC3, clc2-1 clc3-1, and the atg2-1 mutant in Arabidopsis, we found that the autophagy pathway is compromised in the clc2-1 clc3-1 mutant. Subsequently, we demonstrated that CLC2 interacts specifically with ATG8h and ATG8i, two clade II ATG8 isoforms. The CLC2-ATG8h/ATG8i interaction depends on an Atg8-family interacting motif (AIM) present in CLC2 and an AIMs docking site (ADS) present in ATG8h, respectively. In addition, CLC2-GFP is subjected to autophagic degradation and the degradation of GFP-ATG8h is significantly reduced in the clc2-1 clc3-1 mutant. Last, simultaneously knocking out ATG8h and ATG8i enhances disease resistance, corroborating the functional relevance of the CLC2-ATG8h/8i interactions. These findings reveal that CME and the autophagy pathway are intersected via CLC2-ATG8h/8i interactions in Arabidopsis.

Keywords: Autophagy; Clathrin-mediated endocytosis; Immunity; Senescence; cell death; clathrin light chain

DOI: https://doi.org/10.1080/15548627.2024.2414451

Mol Cell. 2024 Oct 17. pii: S1097-2765(24)00703-2. [Epub ahead of print]84(20): 3979-3996.e9

A TBK1-independent primordial function of STING in lysosomal biogenesis.

Bo Lv, William A Dion, Haoxiang Yang, Jinrui Xun, Do-Hyung Kim, Bokai Zhu, Jay Xiaojun Tan.

Stimulator of interferon genes (STING) is activated in many pathophysiological conditions, leading to TBK1-dependent interferon production in higher organisms. However, primordial functions of STING independent of TBK1 are poorly understood. Here, through proteomics and bioinformatics approaches, we identify lysosomal biogenesis as an unexpected function of STING. Transcription factor EB (TFEB), an evolutionarily conserved regulator of lysosomal biogenesis and host defense, is activated by STING from multiple species, including humans, mice, and frogs. STING-mediated TFEB activation is independent of TBK1, but it requires STING trafficking and its conserved proton channel. GABARAP lipidation, stimulated by the channel of STING, is key for STING-dependent TFEB activation. STING stimulates global upregulation of TFEB-target genes, mediating lysosomal biogenesis and autophagy. TFEB supports cell survival during chronic sterile STING activation, a common condition in aging and age-related diseases. These results reveal a primordial function of STING in the biogenesis of lysosomes, essential organelles in immunity and cellular stress resistance.

Keywords: STING; STING channel; TBK1; TFE3; TFEB; autophagy; cGAS; chronic STING signaling; lysosome

DOI: https://doi.org/10.1016/j.molcel.2024.08.026