bims-mecosi 2023-04-23 papers

Issue of 2023‒04‒23
four papers selected by
Verena Kohler

Mol Biol Cell. 2023 Apr 19. mbcE23010029

Multiple tethers of organelle contact sites are involved in α-synuclein toxicity in yeast.

Mara Del Vecchio, Lucia Amado, Alexandra P Cogan, Els Meert, Joelle Rosseels, Vanessa Franssens, Sander K Govers, Joris Winderickx, Ayelén González Montoro.

The protein alpha-synuclein (α-syn) is one of the major factors linked to Parkinson's disease, yet how its misfolding and deposition contribute to the pathology remains largely elusive. Recently, contact sites among organelles were implicated in the development of this disease. Here, we used the budding yeast Saccharomyces cerevisiae, in which organelle contact sites have been characterized extensively, as a model to investigate their role in α-syn cytotoxicity. We observed that lack of specific tethers that anchor the endoplasmic reticulum to the plasma membrane resulted in cells with increased resistance to α-syn expression. Additionally, we found that strains lacking two dual-function proteins involved in contact sites, Mdm10 and Vps39, were resistant to the expression of α-syn. In the case of Mdm10, we found that this is related to its function in mitochondrial protein biogenesis and not to its role as a contact site tether. In contrast, both functions of Vps39, in vesicular transport and as a tether of the vacuole-mitochondria contact site, were required to support α-syn toxicity. Overall, our findings support that inter-organelle communication through membrane contact sites is highly relevant for α-syn mediated toxicity.

DOI: https://doi.org/10.1091/mbc.E23-01-0029

J Cell Sci. 2023 Apr 19. pii: jcs.260578. [Epub ahead of print]

The UbiB family member Cqd1 forms a novel membrane contact site in mitochondria.

Siavash Khosravi, Xenia Chelius, Ann-Katrin Unger, Daniela Rieger, Johanna Frickel, Timo Sachsenheimer, Christian Lüchtenborg, Rico Schieweck, Britta Brügger, Benedikt Westermann, Till Klecker, Walter Neupert, Max E Harner.

Mitochondria are essential organelles of eukaryotic cells that are characterized by their unique and complex membrane system. They are confined from the cytosol by an envelope consisting of two membranes. Signals, metabolites, proteins and lipids have to be transferred across these membranes via proteinaceous contact sites to keep mitochondria functional. In the present study we identified a novel mitochondrial contact site that is formed by the inner membrane protein Cqd1 and the outer membrane proteins Por1 and Om14. Similar to the mitochondrial porin, Por1, Cqd1 is highly conserved, suggesting that this complex is conserved in form and function from yeast to human. Cqd1 is a member of the UbiB protein kinase-like family (also called aarF domain containing kinases). It was recently shown that Cqd1 in cooperation with Cqd2 controls the cellular distribution of coenzyme Q by a yet unknown mechanism. Our data suggest that Cqd1 is additionally involved in phospholipid homeostasis. Moreover, overexpression of CQD1 and CQD2 causes tethering of mitochondria to the endoplasmic reticulum, which might explain the ability of Cqd2 to rescue ERMES deletion phenotypes.

Keywords: Contact sites; Mitochondria; Mitochondrial biogenesis; Mitochondrial morphology; Phospholipids; UbiB protein family

DOI: https://doi.org/10.1242/jcs.260578

Plant Physiol. 2023 Apr 19. pii: kiad238. [Epub ahead of print]

Lipid transport protein ORP2A promotes glucose signaling by facilitating RGS1 degradation.

Qian Yu, Wenjiao Zou, Kui Liu, Jialu Sun, Yanru Chao, Mengyao Sun, Qianqian Zhang, Xiaodong Wang, Xiaofei Wang, Lei Ge.

Heterotrimeric GTP-binding proteins (G proteins) are a group of regulators essential for signal transmission into cells. Regulator of G-protein signaling 1 (AtRGS1) possesses intrinsic GTPase-accelerating protein (GAP) activity and could suppress G-protein and glucose signal transduction in Arabidopsis (Arabidopsis thaliana). However, how AtRGS1 activity is regulated is poorly understood. Here we identified a knockout mutant of OXYSTEROL BINDING PROTEIN-RELATED PROTEIN 2A, orp2a-1, which exhibits similar phenotypes to the arabidopsis g-protein beta 1-2 (agb1-2) mutant. Transgenic lines overexpressing ORP2A displayed short hypocotyls, a hypersensitive response to sugar and lower intracellular AtRGS1 levels than the control. Consistently, ORP2A interacted with AtRGS1 in vitro and in vivo. Tissue-specific expression of two ORP2A alternative splicing isoforms implied functions in controlling organ size and shape. Bioinformatic data and phenotypes of orp2a-1, agb1-2 and the orp2a-1 agb1-2 double mutant revealed the genetic interactions between ORP2A and Gβ in the regulation of G-protein signaling and sugar response. Both alternative protein isoforms of ORP2A localized in the ER, plasma membrane (PM) and ER-PM Contact Sites and interacted with vesicle-associated membrane protein-associated protein 27-1 (VAP27-1) in vivo and in vitro through their FFAT-like motif. ORP2A also displayed differential phosphatidyl phosphoinositide binding activity mediated by the PH domain in vitro. Taken together, the Arabidopsis membrane protein ORP2A interacts with AtRGS1 and VAP27-1 to positively regulate G-protein and sugar signaling by facilitating AtRGS1 degradation.

DOI: https://doi.org/10.1093/plphys/kiad238

Nat Cell Biol. 2023 Apr 20.

Nuclear and cytoplasmic spatial protein quality control is coordinated by nuclear-vacuolar junctions and perinuclear ESCRT.

Emily M Sontag, Fabián Morales-Polanco, Jian-Hua Chen, Gerry McDermott, Patrick T Dolan, Daniel Gestaut, Mark A Le Gros, Carolyn Larabell, Judith Frydman.

Effective protein quality control (PQC), essential for cellular health, relies on spatial sequestration of misfolded proteins into defined inclusions. Here we reveal the coordination of nuclear and cytoplasmic spatial PQC. Cytoplasmic misfolded proteins concentrate in a cytoplasmic juxtanuclear quality control compartment, while nuclear misfolded proteins sequester into an intranuclear quality control compartment (INQ). Particle tracking reveals that INQ and the juxtanuclear quality control compartment converge to face each other across the nuclear envelope at a site proximal to the nuclear-vacuolar junction marked by perinuclear ESCRT-II/III protein Chm7. Strikingly, convergence at nuclear-vacuolar junction contacts facilitates VPS4-dependent vacuolar clearance of misfolded cytoplasmic and nuclear proteins, the latter entailing extrusion of nuclear INQ into the vacuole. Finding that nuclear-vacuolar contact sites are cellular hubs of spatial PQC to facilitate vacuolar clearance of nuclear and cytoplasmic inclusions highlights the role of cellular architecture in proteostasis maintenance.

DOI: https://doi.org/10.1038/s41556-023-01128-6