bims-mecosi 2023-03-05 papers

Issue of 2023–03–05
eight papers selected by
Verena Kohler, University of Graz

Cell Mol Life Sci. 2023 Feb 28. 80(3): 77

ORP9 and ORP10 form a heterocomplex to transfer phosphatidylinositol 4-phosphate at ER-TGN contact sites.

Ruyue He, Furong Liu, Hui Wang, Shuai Huang, Kai Xu, Conggang Zhang, Yinghui Liu, Haijia Yu.

Oxysterol-binding protein (OSBP) and its related proteins (ORPs) are a family of lipid transfer proteins (LTPs) that mediate non-vesicular lipid transport. ORP9 and ORP10, members of the OSBP/ORPs family, are located at the endoplasmic reticulum (ER)-trans-Golgi network (TGN) membrane contact sites (MCSs). It remained unclear how they mediate lipid transport. In this work, we discovered that ORP9 and ORP10 form a binary complex through intermolecular coiled-coil (CC) domain-CC domain interaction. The PH domains of ORP9 and ORP10 specially interact with phosphatidylinositol 4-phosphate (PI4P), mediating the TGN targeting. The ORP9-ORP10 complex plays a critical role in regulating PI4P levels at the TGN. Using in vitro reconstitution assays, we observed that while full-length ORP9 efficiently transferred PI4P between two apposed membranes, the lipid transfer kinetics was further accelerated by ORP10. Interestingly, our data showed that the PH domains of ORP9 and ORP10 participate in membrane tethering simultaneously, whereas ORDs of both ORP9 and ORP10 are required for lipid transport. Furthermore, our data showed that the depletion of ORP9 and ORP10 led to increased vesicle transport to the plasma membrane (PM). These findings demonstrate that ORP9 and ORP10 form a binary complex through the CC domains, maintaining PI4P homeostasis at ER-TGN MCSs and regulating vesicle trafficking.

Keywords: Coiled-coil domain; Lipid homeostasis; Lipid transport; Membrane contact sites; OSBP/ORPs; Vesicle trafficking

DOI: https://doi.org/10.1007/s00018-023-04728-5

Curr Opin Cell Biol. 2023 Feb 25. pii: S0955-0674(23)00004-2. [Epub ahead of print]80 102155

Endosome biogenesis is controlled by ER and the cytoskeleton at tripartite junctions.

Jonathan F Striepen, Gia K Voeltz.

The plasma membrane (PM) and its associated cargo are internalized into small vesicles via endocytosis funneling cargo into endosomes. The endosomal system must efficiently deliver cargos, as well as recycle cargo receptors and membrane to maintain homeostasis. In animal cells, endosome trafficking, maturation, and cargo recycling rely on the actin and microtubule cytoskeleton. Microtubules and their associated motor proteins provide the roads on which endosomes move and fuse during cargo sorting and delivery. In addition, highly dynamic assemblies of actin adjust the shape of the endosomal membrane to promote cargo segregation into budding domains allowing for receptor recycling. Recent work has revealed that the endoplasmic reticulum (ER) frequently acts as an intermediary between endosomes and their cytoskeletal regulators via membrane contact sites (MCSs). This review will discuss the factors which form these tripartite junction between the ER, endosomes, and the cytoskeleton as well as their function.

DOI: https://doi.org/10.1016/j.ceb.2023.102155

J Exp Bot. 2023 Feb 27. pii: erad068. [Epub ahead of print]

ER-membrane contact sites: cross talk between Membrane-bound organelles in plant cells.

Jiahui Bian, Xiao Su, Xiaoyan Yuan, Yuan Zhang, Jinxing Lin, Xiaojuan Li.

Eukaryotic cells contain organelles surrounded by monolayer or bilayer membranes. Organelles take part in highly dynamic and organized interactions at membrane contact sites, which play vital roles during development and response to stress. The endoplasmic reticulum extends throughout the cell and acts as an architectural scaffold to maintain the spatial distribution of other membrane-bound organelles. In this review, we highlight the structural organization, dynamics, and physiological functions of membrane contact sites between the endoplasmic reticulum and various membrane-bound organelles, especially recent advances in plants. We briefly introduce how the combined use of dynamic and static imaging techniques can enable monitoring of the cross-talk between organelles via membrane contact sites. Finally, we discuss future directions for research fields related to membrane contacts.

Keywords: in vivo ; Dynamics; Endoplasmic reticulum; Membrane contact sites; Morphology; Organelle interaction

DOI: https://doi.org/10.1093/jxb/erad068

J Cell Mol Med. 2023 Feb 27.

Mitochondria-associated endoplasmic reticulum membrane: Overview and inextricable link with cancer.

Xi Yang, Jing Zhuang, Weilong Song, Wangjie Shen, Wei Wu, Hong Shen, Shuwen Han.

The mitochondrial-associated membrane (MAM) is a physical platform that facilitates communication between the endoplasmic reticulum (ER) and mitochondria. It is enriched with many proteins and enzymes and plays an important role in the regulation of several fundamental physiological processes, such as calcium (Ca2+ ) transfer, lipid synthesis, cellular autophagy and ER stress. Accumulating evidence suggests that oncogenes and suppressor genes are present at the ER-mitochondrial contact site, and their alterations can affect Ca2+ flux, lipid homeostasis, and the dysregulation of mitochondrial dynamics, thereby influencing the fate of cancer cells. Understanding the fundamental role of MAM-resident proteins in tumorigenesis could support the search for novel therapeutic targets in cancer. In this review, we summarize the basic structure of MAM and the core functions of MAM-resident proteins in tumorigenesis. In addition, we discuss the mechanisms by which natural compounds promote cancer cell apoptosis from the perspective of ER stress.

Keywords: ER stress; autophagy; calcium transfer; cancer; endoplasmic reticulum; lipid synthesis; mitochondria; mitochondrial-associated membrane

DOI: https://doi.org/10.1111/jcmm.17696

Oncol Rep. 2023 Apr;pii: 77. [Epub ahead of print]49(4):

Key genes expressed in mitochondria‑endoplasmic reticulum contact sites in cancer (Review).

Sophia Themistocleous, Panayiota Christodoulou, Theodora-Christina Kyriakou, Charalampos Filippou, Apostolos Zaravinos, Andreas Yiallouris.

Cell fate is critically affected by mitochondrial activity, from ATP production to metabolism, Ca2+ homeostasis and signaling. These actions are regulated by proteins expressed in mitochondria (Mt)‑endoplasmic reticulum contact sites (MERCSs). The literature supports the fact that disruption to the physiology of the Mt and/or MERCSs can be due to alterations in the Ca2+ influx/efflux, which further regulates autophagy and apoptosis activity. The current review presents the findings of numerous studies with regard to the involvement of proteins positioned in MERCSs and how they express anti‑ and pro‑apoptotic properties by adjusting Ca2+ across membranes. The review also explores the involvement of mitochondrial proteins as hot spots in cancer development, cell death and/or survival, and the method via which they can potentially be targeted as a therapeutic option.

Keywords: Ca2+ singling; MERCS; MERCS genes; cancer

DOI: https://doi.org/10.3892/or.2023.8514

mSphere. 2023 Feb 28. e0000323

Homologues of the Chlamydia trachomatis and Chlamydia muridarum Inclusion Membrane Protein IncS Are Interchangeable for Early Development but Not for Inclusion Stability in the Late Developmental Cycle.

María Eugenia Cortina, Isabelle Derré.

Chlamydia trachomatis is an obligate intracellular bacterium, which undergoes a biphasic developmental cycle inside a vacuole termed the inclusion. Chlamydia-specific effector proteins embedded into the inclusion membrane, the Inc proteins, facilitate inclusion interaction with cellular organelles. A subset of Inc proteins engages with specific host factors at the endoplasmic reticulum (ER)-inclusion membrane contact site (MCS), which is a discrete point of contact between the inclusion membrane and the endoplasmic reticulum (ER). Here, we report that the C. trachomatis Inc protein CTL0402/IncSCt is a novel component of the ER-inclusion MCS that specifically interacts with and recruits STIM1, a previously identified host component of the ER-inclusion MCS with an unassigned interacting partner at the inclusion membrane. In comparison, the Chlamydia muridarum IncS homologue (TC0424/IncSCm) does not interact with or recruit STIM1 to the inclusion, indicating species specificity. To further investigate IncS function and overcome the recently reported early developmental defect of the incS mutant, we achieved temporal complementation by expressing IncS exclusively during the early stages of the developmental cycle. Additionally, we used allelic exchange to replace the incSCt open reading frame with incSCm in the C. trachomatis chromosome. Inclusions harboring either of these strains progressed through the developmental cycle but were STIM1 negative and displayed increased inclusion lysis 48 h postinfection. Expression of incSCt in trans complemented these phenotypes. Altogether, our results indicate that IncS is necessary and sufficient to recruit STIM1 to C. trachomatis inclusion and that IncS plays an early developmental role conserved in C. trachomatis and C. muridarum and a late role in inclusion stability specific to C. trachomatis. IMPORTANCE Obligate intracellular pathogens strictly rely on the host for replication. Specialized pathogen-encoded effector proteins play a central role in sophisticated mechanisms of host cell manipulation. In Chlamydia, a subset of these effector proteins, the inclusion membrane proteins, are embedded in the membrane of the vacuole in which the bacteria replicate. Chlamydia encodes 50 to 100 putative Inc proteins. Many are conserved among species, including the human and mouse pathogens Chlamydia trachomatis and Chlamydia muridarum, respectively. However, whether the function(s) of Inc proteins is indeed conserved among species is poorly understood. Here, we characterized the function of the Inc protein IncS conserved in C. trachomatis and C. muridarum. Our work reveals that a single effector protein can play multiple functions at various stages of the developmental cycle. However, these functions are not necessarily conserved across species, suggesting a complex evolutionary path among Chlamydia species.

Keywords: Chlamydia developmental cycle; Chlamydia genome editing; Chlamydia muridarum; Chlamydia trachomatis; ER-inclusion membrane contact sites; FRAEM/FLAEM; IncS/CTL0402/TC0424; STIM1; effector proteins; inclusion membrane proteins; species specificity; temporal mutant complementation

DOI: https://doi.org/10.1128/msphere.00003-23

Comput Struct Biotechnol J. 2023 ;21 1670-1677

The interconnection of endoplasmic reticulum and microtubule and its implication in Hereditary Spastic Paraplegia.

Xinjian Wang, Chengyu Fan, Yanfen Liu, Yan Zou.

The endoplasmic reticulum (ER) and microtubule (MT) network form extensive contact with each other and their interconnection plays a pivotal role in ER maintenance and distribution as well as MT stability. The ER participates in a variety of biological processes including protein folding and processing, lipid biosynthesis, and Ca2+ storage. MTs specifically regulate cellular architecture, provide routes for transport of molecules or organelles, and mediate signaling events. The ER morphology and dynamics are regulated by a class of ER shaping proteins, which also provide the physical contact structure for linking of ER and MT. In addition to these ER-localized and MT-binding proteins, specific motor proteins and adaptor-linking proteins also mediate bidirectional communication between the two structures. In this review, we summarize the current understanding of the structure and function of ER-MT interconnection. We further highlight the morphologic factors which coordinate the ER-MT network and maintain the normal physiological function of neurons, with their defect causing neurodegenerative diseases such as Hereditary Spastic Paraplegia (HSP). These findings promote our understanding of the pathogenesis of HSP and provide important therapeutic targets for treatment of these diseases.

Keywords: ER membrane protein; ER shaping proteins; ER-MT; Endoplasmic Reticulum; HSP; Hereditary Spastic Paraplegia; Microtubule dynamics

DOI: https://doi.org/10.1016/j.csbj.2023.02.025

Physiology (Bethesda). 2023 May 01. 38(3): 0

Organelle Communication: Joined in Sickness and in Health.

Roberto Bravo-Sagua, Camila Lopez-Crisosto, Alfredo Criollo, Reiko Inagi, Sergio Lavandero.

Organelles are membrane-lined structures that compartmentalize subcellular biochemical functions. Therefore, interorganelle communication is crucial for cellular responses that require the coordination of such functions. Multiple principles govern interorganelle interactions, which arise from the complex nature of organelles: position, multilingualism, continuity, heterogeneity, proximity, and bidirectionality, among others. Given their importance, alterations in organelle communication have been linked to many diseases. Among the different types of contacts, endoplasmic reticulum mitochondria interactions are the best known; however, mounting evidence indicates that other organelles also have something to say in the pathophysiological conversation.

Keywords: communication; compartmentalization; organelle; pathology; signaling

DOI: https://doi.org/10.1152/physiol.00024.2022