scholarly journals Nup358 regulates remodelling of ER-mitochondrial contact sites and autophagy

2021 ◽  
Author(s):  
Misha Kalarikkal ◽  
Rimpi Saikia ◽  
Pallavi Varshney ◽  
Prathamesh Dhamale ◽  
Amitabha Majumdar ◽  
...  
Keyword(s):  
Growth Factor ◽  
Calcium Homeostasis ◽  
Lipid Transport ◽  
Annulate Lamellae ◽  
Subcellular Structure ◽  
Cellular Processes ◽  
Contact Sites

The contact sites between ER and mitochondria regulate several cellular processes including inter-organelle lipid transport, calcium homeostasis and autophagy. However, the mechanisms that regulate the dynamics and functions of these contact sites remain unresolved. We show that annulate lamellae (AL), a relatively unexplored subcellular structure representing subdomains of ER enriched with a subset of nucleoporins, are present at ER-mitochondria contact sites (ERMCS). Depletion of one of the AL-resident nucleoporins, Nup358, results in increased contacts between ER and mitochondria. Mechanistically, Nup358 modulates ERMCS dynamics by restricting mTORC2/Akt signalling. Our results suggest that growth factor-mediated remodelling of ERMCS depends on a reciprocal binding of Nup358 and mTOR to the ERMCS tethering complex consisting of VAPB and PTPIP51. Furthermore, Nup358 also interacts with IP3R, an ERMCS-enriched Ca2+ channel, and controls Ca2+ release from the ER. Consequently, depletion of Nup358 leads to elevated cytoplasmic Ca2+ and autophagy via activation of Ca2+/CaMKK2/AMPK axis. Our study thus uncovers a novel role for AL, particularly for Nup358, in regulating mTORC2-mediated ERMCS remodelling and Ca2+-directed autophagy, possibly via independent mechanisms.

scholarly journals Miga-mediated endoplasmic reticulum–mitochondria contact sites regulate neuronal homeostasis

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Lingna Xu ◽  
Xi Wang ◽  
Jia Zhou ◽  
Yunyi Qiu ◽  
Weina Shang ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Mammalian Cells ◽  
Mitochondrial Dynamics ◽  
Molecular Organization ◽  
Lipid Transport ◽  
Cellular Processes ◽  
Contact Sites ◽  
Neuronal Homeostasis ◽  
Higher Eukaryotes ◽  
Lateral Sclerosis

Endoplasmic reticulum (ER)–mitochondria contact sites (ERMCSs) are crucial for multiple cellular processes such as calcium signaling, lipid transport, and mitochondrial dynamics. However, the molecular organization, functions, regulation of ERMCS, and the physiological roles of altered ERMCSs are not fully understood in higher eukaryotes. We found that Miga, a mitochondrion located protein, markedly increases ERMCSs and causes severe neurodegeneration upon overexpression in fly eyes. Miga interacts with an ER protein Vap33 through its FFAT-like motif and an amyotrophic lateral sclerosis (ALS) disease related Vap33 mutation considerably reduces its interaction with Miga. Multiple serine residues inside and near the Miga FFAT motif were phosphorylated, which is required for its interaction with Vap33 and Miga-mediated ERMCS formation. The interaction between Vap33 and Miga promoted further phosphorylation of upstream serine/threonine clusters, which fine-tuned Miga activity. Protein kinases CKI and CaMKII contribute to Miga hyperphosphorylation. MIGA2, encoded by the miga mammalian ortholog, has conserved functions in mammalian cells. We propose a model that shows Miga interacts with Vap33 to mediate ERMCSs and excessive ERMCSs lead to neurodegeneration.

scholarly journals The Interactome of the VAP Family of Proteins: An Overview

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1780
Author(s):  
Christina James ◽  
Ralph H. Kehlenbach
Keyword(s):  
Endoplasmic Reticulum ◽  
Calcium Homeostasis ◽  
In Silico ◽  
Lipid Transport ◽  
Biological Processes ◽  
Close Apposition ◽  
Membrane Contact Sites ◽  
Contact Sites ◽  
Associated Proteins ◽  
Membrane Contact

Membrane contact sites (MCS) are sites of close apposition of two organelles that help in lipid transport and synthesis, calcium homeostasis and several other biological processes. The VAMP-associated proteins (VAPs) VAPA, VAPB, MOSPD2 and the recently described MOSPD1 and MOSPD3 are tether proteins of MCSs that are mainly found at the endoplasmic reticulum (ER). VAPs interact with various proteins with a motif called FFAT (two phenylalanines in an acidic tract), recruiting the associated organelle to the ER. In addition to the conventional FFAT motif, the recently described FFNT (two phenylalanines in a neutral tract) and phospho-FFAT motifs contribute to the interaction with VAPs. In this review, we summarize and compare the recent interactome studies described for VAPs, including in silico and proximity labeling methods. Collectively, the interaction repertoire of VAPs is very diverse and highlights the complexity of interactions mediated by the different FFAT motifs to the VAPs.

Non-vesicular lipid trafficking at the endoplasmic reticulum–mitochondria interface

2018 ◽  
Vol 46 (2) ◽  
pp. 437-452 ◽  
Author(s):  
Francesca Giordano
Keyword(s):  
Endoplasmic Reticulum ◽  
Lipid Transport ◽  
Lipid Transfer ◽  
Lipid Transfer Proteins ◽  
Transport Pathways ◽  
Lipid Trafficking ◽  
Cellular Processes ◽  
Membrane Contact Sites ◽  
Contact Sites ◽  
Membrane Contact

Mitochondria are highly dynamic organelles involved in various cellular processes such as energy production, regulation of calcium homeostasis, lipid trafficking, and apoptosis. To fulfill all these functions and preserve their morphology and dynamic behavior, mitochondria need to maintain a defined protein and lipid composition in both their membranes. The maintenance of mitochondrial membrane identity requires a selective and regulated transport of specific lipids from/to the endoplasmic reticulum (ER) and across the mitochondria outer and inner membranes. Since they are not integrated in the classical vesicular trafficking routes, mitochondria exchange lipids with the ER at sites of close apposition called membrane contact sites. Deregulation of such transport activities results in several pathologies including cancer and neurodegenerative disorders. However, we are just starting to understand the function of ER–mitochondria contact sites in lipid transport, what are the proteins involved and how they are regulated. In this review, we summarize recent insights into lipid transport pathways at the ER–mitochondria interface and discuss the implication of recently identified lipid transfer proteins in these processes.

Two new isoforms of the human hepatoma-derived growth factor interact with components of the cytoskeleton

2016 ◽  
Vol 397 (5) ◽  
pp. 417-436 ◽  
Author(s):  
Jessica Nüße ◽  
Ursula Mirastschijski ◽  
Mario Waespy ◽  
Janina Oetjen ◽  
Nadine Brandes ◽  
...  
Keyword(s):  
Growth Factor ◽  
Ribosome Biogenesis ◽  
Transcriptional Control ◽  
Splice Variants ◽  
Retrograde Transport ◽  
Interaction Patterns ◽  
Cytoskeleton Organization ◽  
Cellular Processes ◽  
Messenger Ribonucleoprotein ◽  
Transport Site

Abstract Hepatoma-derived growth factor (HDGF) is involved in diverse, apparently unrelated processes, such as cell proliferation, apoptosis, DNA-repair, transcriptional control, ribosome biogenesis and cell migration. Most of the interactions of HDGF with diverse molecules has been assigned to the hath region of HDGF. In this study we describe two previously unknown HDGF isoforms, HDGF-B and HDGF-C, generated via alternative splicing with structurally unrelated N-terminal regions of their hath region, which is clearly different from the well described isoform, HDGF-A. In silico modeling revealed striking differences near the PHWP motif, an essential part of the binding site for glycosaminoglycans and DNA/RNA. This observation prompted the hypothesis that these isoforms would have distinct interaction patterns with correspondingly diverse roles on cellular processes. Indeed, we discovered specific associations of HDGF-B and HDGF-C with cytoskeleton elements, such as tubulin and dynein, suggesting previously unknown functions of HDGF in retrograde transport, site directed localization and/or cytoskeleton organization. In contrast, the main isoform HDGF-A does not interact directly with the cytoskeleton, but via RNA with messenger ribonucleoprotein (mRNP) complexes. In summary, the discovery of HDGF splice variants with their discrete binding activities and subcellular distributions opened new avenues for understanding its biological function and importance.

The Tissue Factor Pathway and Wound Healing

2017 ◽  
Vol 44 (02) ◽  
pp. 142-150 ◽  
Author(s):  
Maureane Hoffman
Keyword(s):  
Wound Healing ◽  
Growth Factor ◽  
Cell Signaling ◽  
Tissue Factor ◽  
Blood Coagulation ◽  
Host Response ◽  
Cellular Processes ◽  
Injured Tissue ◽  
Tissue Factor Pathway

AbstractThe role of tissue factor (TF) as the major initiator of hemostatic blood coagulation is well recognized. The ability to form an adequate hemostatic clot is essential to the normal healing of an injury by staunching bleeding, stabilizing the injured tissue, and serving as a scaffold for repair processes. Also, some molecules produced during hemostasis, particularly thrombin, have cytokine and growth factor-like activities that contribute to inflammation and repair. However, TF itself has activities as a regulator of cellular processes via direct signaling, as well as by facilitating activation of proteolytically activated receptors by activated factors VII and X. The importance of hemostasis in the host response to injury makes it very difficult to separate the hemostatic from nonhemostatic effects of TF on wound healing. The literature in this area remains sparse but suggests that TF influences the course and tempo of healing by cell signaling events that impact inflammation, epithelialization, and angiogenesis.

scholarly journals PINK1/Parkin Mediated Mitophagy, Ca2+ Signalling, and ER–Mitochondria Contacts in Parkinson’s Disease

2020 ◽  
Vol 21 (5) ◽  
pp. 1772 ◽  
Author(s):  
Lucia Barazzuol ◽  
Flavia Giamogante ◽  
Marisa Brini ◽  
Tito Calì
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Endoplasmic Reticulum ◽  
Neurodegenerative Diseases ◽  
Current Knowledge ◽  
Phosphatase And Tensin Homolog ◽  
Cellular Processes ◽  
Selective Degradation ◽  
Contact Sites ◽  
Tensin Homolog

Endoplasmic reticulum (ER)–mitochondria contact sites are critical structures for cellular function. They are implicated in a plethora of cellular processes, including Ca2+ signalling and mitophagy, the selective degradation of damaged mitochondria. Phosphatase and tensin homolog (PTEN)-induced kinase (PINK) and Parkin proteins, whose mutations are associated with familial forms of Parkinson’s disease, are two of the best characterized mitophagy players. They accumulate at ER–mitochondria contact sites and modulate organelles crosstalk. Alterations in ER–mitochondria tethering are a common hallmark of many neurodegenerative diseases including Parkinson’s disease. Here, we summarize the current knowledge on the involvement of PINK1 and Parkin at the ER–mitochondria contact sites and their role in the modulation of Ca2+ signalling and mitophagy.

scholarly journals Modulation of the TGF-β signaling pathway by long noncoding RNA in hepatocellular carcinoma

2020 ◽  
Vol 8 (1) ◽  
Author(s):  
Mengzhen Han ◽  
Zhibin Liao ◽  
Furong Liu ◽  
Xiaoping Chen ◽  
Bixiang Zhang
Keyword(s):  
Hepatocellular Carcinoma ◽  
Growth Factor ◽  
Noncoding Rna ◽  
Poor Prognosis ◽  
Therapeutic Strategy ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Cellular Processes ◽  
Therapy Targets ◽  
Non Coding Rnas

AbstractHepatocellular carcinoma (HCC) is a type of liver cancer with poor prognosis. There have been demonstrated to exist many possible mechanisms in HCC tumorigenesis, and recent investigations have provided some promising therapy targets. However, further mechanisms remain to be researched to improve the therapeutic strategy and diagnosis of HCC. Transforming growth factor-β (TGF-β) is a pleiotropic cytokine which plays critical roles in networks of different cellular processes, and TGF-β signaling has been found to participate in tumor initiation and development of HCC in recent years. Moreover, among the molecules and signaling pathways, researchers paid more attention to lncRNAs (long non-coding RNAs), but the connection between lncRNAs and TGF-βremain poorly understood. In this review, we conclude the malignant procedure which lncRNAs and TGF-β involved in, and summarize the mechanisms of lncRNAs and TGF-βin HCC initiation and development. Furthermore, the interaction between lncRNA and TGF-β are paid more attention, and the potential therapy targets are mentioned.

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