bims-mecosi 2024-02-18 papers

Issue of 2024–02–18
five papers selected by
Verena Kohler, Umeå University

Dev Cell. 2024 Feb 03. pii: S1534-5807(24)00034-0. [Epub ahead of print]

LDO proteins and Vac8 form a vacuole-lipid droplet contact site to enable starvation-induced lipophagy in yeast.

Irene Álvarez-Guerra, Emma Block, Filomena Broeskamp, Sonja Gabrijelčič, Terence Infant, Ana de Ory, Lukas Habernig, Claes Andréasson, Tim P Levine, Johanna L Höög, Sabrina Büttner.

Lipid droplets (LDs) are fat storage organelles critical for energy and lipid metabolism. Upon nutrient exhaustion, cells consume LDs via gradual lipolysis or via lipophagy, the en bloc uptake of LDs into the vacuole. Here, we show that LDs dock to the vacuolar membrane via a contact site that is required for lipophagy in yeast. The LD-localized LDO proteins carry an intrinsically disordered region that directly binds vacuolar Vac8 to form vCLIP, the vacuolar-LD contact site. Nutrient limitation drives vCLIP formation, and its inactivation blocks lipophagy, resulting in impaired caloric restriction-induced longevity. We establish a functional link between lipophagy and microautophagy of the nucleus, both requiring Vac8 to form respective contact sites upon metabolic stress. In sum, we identify the tethering machinery of vCLIP and find that Vac8 provides a platform for multiple and competing contact sites associated with autophagy.

Keywords: Ldo16; Ldo45; NVJ; lipid droplets; lipophagy; membrane contact sites; nucleus-vacuole junction; nutrient limitation; vCLIP; vacuole-lipid droplet contact site

DOI: https://doi.org/10.1016/j.devcel.2024.01.014

J Mol Biol. 2024 Feb 09. pii: S0022-2836(24)00061-5. [Epub ahead of print] 168489

The role of ATG9 vesicles in autophagosome biogenesis.

Elisabeth Holzer, Sascha Martens, Susanna Tulli.

Autophagy mediates the degradation and recycling of cellular material in the lysosomal system. Dysfunctional autophagy is associated with a plethora of diseases including uncontrolled infections, cancer and neurodegeneration. In macroautophagy (hereafter autophagy) this material is encapsulated in double membrane vesicles, the autophagosomes, which form upon induction of autophagy. The precursors to autophagosomes, referred to as phagophores, first appear as small flattened membrane cisternae, which gradually enclose the cargo material as they grow. The assembly of phagophores during autophagy initiation has been a major subject of investigation over the past decades. A special focus has been ATG9, the only conserved transmembrane protein among the core machinery. The majority of ATG9 localizes to small Golgi-derived vesicles. Here we review the recent advances and breakthroughs regarding our understanding of how ATG9 and the vesicles it resides in serve to assemble the autophagy machinery and to establish membrane contact sites for autophagosome biogenesis. We also highlight open questions in the field that need to be addressed in the years to come.

Keywords: ATG2; ATG9; Macroautophagy; endoplasmic reticulum; lipid synthesis; lipid transfer; membrane contact site; membrane traffic

DOI: https://doi.org/10.1016/j.jmb.2024.168489

bioRxiv. 2024 Feb 04. pii: 2024.02.02.578646. [Epub ahead of print]

BRD4-mediated epigenetic regulation of endoplasmic reticulum-mitochondria contact sites is governed by the mitochondrial complex III.

Brandon Chen, Theophilus M Lynn-Nguyen, Pankaj Jadhav, Benjamin S Halligan, Nicholas J Rossiter, Rachel M Guerra, Sergei Koshkin, Imhoi Koo, Pietro Morlacchi, David A Hanna, Jason Lin, Ruma Banerjee, David J Pagliarini, Andrew D Patterson, Shyamal Mosalaganti, Jonathan Z Sexton, Tito Calì, Costas A Lyssiotis, Yatrik M Shah.

Inter-organellar communication is critical for cellular metabolic homeostasis. One of the most abundant inter-organellar interactions are those at the endoplasmic reticulum and mitochondria contact sites (ERMCS). However, a detailed understanding of the mechanisms governing ERMCS regulation and their roles in cellular metabolism are limited by a lack of tools that permit temporal induction and reversal. Through unbiased screening approaches, we identified fedratinib, an FDA-approved drug, that dramatically increases ERMCS abundance by inhibiting the epigenetic modifier BRD4. Fedratinib rapidly and reversibly modulates mitochondrial and ER morphology and alters metabolic homeostasis. Moreover, ERMCS modulation depends on mitochondria electron transport chain complex III function. Comparison of fedratinib activity to other reported inducers of ERMCS revealed common mechanisms of induction and function, providing clarity and union to a growing body of experimental observations. In total, our results uncovered a novel epigenetic signaling pathway and an endogenous metabolic regulator that connects ERMCS and cellular metabolism.

DOI: https://doi.org/10.1101/2024.02.02.578646

Front Cell Dev Biol. 2023 ;11 1211498

Annexin A7 mediates lysosome repair independently of ESCRT-III.

Malene Laage Ebstrup, Stine Lauritzen Sønder, Ditte Louise Fogde, Anne Sofie Busk Heitmann, Tiina Naumanen Dietrich, Catarina Dias, Marja Jäättelä, Kenji Maeda, Jesper Nylandsted.

Lysosomes are crucial organelles essential for various cellular processes, and any damage to them can severely compromise cell viability. This study uncovers a previously unrecognized function of the calcium- and phospholipid-binding protein Annexin A7 in lysosome repair, which operates independently of the Endosomal Sorting Complex Required for Transport (ESCRT) machinery. Our research reveals that Annexin A7 plays a role in repairing damaged lysosomes, different from its role in repairing the plasma membrane, where it facilitates repair through the recruitment of ESCRT-III components. Notably, our findings strongly suggest that Annexin A7, like the ESCRT machinery, is dispensable for membrane contact site formation within the newly discovered phosphoinositide-initiated membrane tethering and lipid transport (PITT) pathway. Instead, we speculate that Annexin A7 is recruited to damaged lysosomes and promotes repair through its membrane curvature and cross-linking capabilities. Our findings provide new insights into the diverse mechanisms underlying lysosomal membrane repair and highlight the multifunctional role of Annexin A7 in membrane repair.

Keywords: Annexin A7; ER-lysosome membrane contact sites (MCSs); L-Leucyl-L-Leucine O-methyl ester (LLOMe); endosomal sorting complexes required for transport III (ESCRT-III); lysosomal integrity; lysosomal membrane permeabilization; lysosome membrane repair; organelle repair

DOI: https://doi.org/10.3389/fcell.2023.1211498

FEBS Lett. 2024 Feb 14.

CIDE proteins and their regulatory mechanisms in lipid droplet fusion and growth.

Li Xu, Lizhen Li, Lingzhi Wu, Peng Li, Feng-Jung Chen.

The cell death-inducing DFF45-like effector (CIDE) proteins, including Cidea, Cideb, and Cidec/Fsp27, regulate various aspects of lipid homeostasis, including lipid storage, lipolysis, and lipid secretion. This review focuses on the physiological roles of CIDE proteins based on studies on knockout mouse models and human patients bearing CIDE mutations. The primary cellular function of CIDE proteins is to localize to lipid droplets (LDs) and to control LD fusion and growth across different cell types. We propose a four-step process of LD fusion, characterized by (a) the recruitment of CIDE proteins to the LD surface and CIDE movement, (b) the enrichment and condensate formation of CIDE proteins to form LD fusion plates at LD-LD contact sites, (c) lipid transfer through lipid-permeable passageways within the fusion plates, and (d) the completion of LD fusion. Lastly, we outline CIDE-interacting proteins as regulatory factors, as well as their contribution in LD fusion.

Keywords: CIDE; lipid droplet fusion; lipid transfer; phase separation

DOI: https://doi.org/10.1002/1873-3468.14823