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1.
Nat Commun ; 13(1): 4720, 2022 Aug 11.
Article in English | MEDLINE | ID: covidwho-1991593

ABSTRACT

Membrane contact sites (MCSs) link organelles to coordinate cellular functions across space and time. Although viruses remodel organelles for their replication cycles, MCSs remain largely unexplored during infections. Here, we design a targeted proteomics platform for measuring MCS proteins at all organelles simultaneously and define functional virus-driven MCS alterations by the ancient beta-herpesvirus human cytomegalovirus (HCMV). Integration with super-resolution microscopy and comparisons to herpes simplex virus (HSV-1), Influenza A, and beta-coronavirus HCoV-OC43 infections reveals time-sensitive contact regulation that allows switching anti- to pro-viral organelle functions. We uncover a stabilized mitochondria-ER encapsulation structure (MENC). As HCMV infection progresses, MENCs become the predominant mitochondria-ER contact phenotype and sequentially recruit the tethering partners VAP-B and PTPIP51, supporting virus production. However, premature ER-mitochondria tethering activates STING and interferon response, priming cells against infection. At peroxisomes, ACBD5-mediated ER contacts balance peroxisome proliferation versus membrane expansion, with ACBD5 impacting the titers of each virus tested.


Subject(s)
Cytomegalovirus Infections , Herpes Simplex , Herpesviridae Infections , Viruses , Cytomegalovirus/physiology , Herpesviridae Infections/metabolism , Humans , Organelles , Peroxisomes/metabolism
2.
J Cell Biol ; 221(6)2022 06 06.
Article in English | MEDLINE | ID: covidwho-1960887

ABSTRACT

ß-coronaviruses reshape host cell endomembranes to form double-membrane vesicles (DMVs) for genome replication and transcription. Ectopically expressed viral nonstructural proteins nsp3 and nsp4 interact to zipper and bend the ER for DMV biogenesis. Genome-wide screens revealed the autophagy proteins VMP1 and TMEM41B as important host factors for SARS-CoV-2 infection. Here, we demonstrated that DMV biogenesis, induced by virus infection or expression of nsp3/4, is impaired in the VMP1 KO or TMEM41B KO cells. In VMP1 KO cells, the nsp3/4 complex forms normally, but the zippered ER fails to close into DMVs. In TMEM41B KO cells, the nsp3-nsp4 interaction is reduced and DMV formation is suppressed. Thus, VMP1 and TMEM41B function at different steps during DMV formation. VMP1 was shown to regulate cross-membrane phosphatidylserine (PS) distribution. Inhibiting PS synthesis partially rescues the DMV defects in VMP1 KO cells, suggesting that PS participates in DMV formation. We provide molecular insights into the collaboration of host factors with viral proteins to remodel host organelles.


Subject(s)
COVID-19 , Membrane Proteins , SARS-CoV-2 , Viral Replication Compartments , Autophagy/genetics , Humans , Membrane Proteins/genetics , Membrane Proteins/metabolism , Organelles/metabolism , Phosphatidylserines , SARS-CoV-2/physiology , Viral Nonstructural Proteins/genetics , Virus Replication
3.
Viruses ; 14(5)2022 05 19.
Article in English | MEDLINE | ID: covidwho-1903492

ABSTRACT

Since the end of 2019, the whole world has been struggling with the life-threatening pandemic amongst all age groups and geographic areas caused by Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2). The Coronavirus Disease 2019 (COVID-19) pandemic, which has led to more than 468 million cases and over 6 million deaths reported worldwide (as of 20 March 2022), is one of the greatest threats to human health in history. Meanwhile, the lack of specific and irresistible treatment modalities provoked concentrated efforts in scientists around the world. Various mechanisms of cell entry and cellular dysfunction were initially proclaimed. Especially, mitochondria and cell membrane are crucial for the course of infection. The SARS-CoV-2 invasion depends on angiotensin converting enzyme 2 (ACE2), transmembrane serine protease 2 (TMPRSS2), and cluster of differentiation 147 (CD147), expressed on host cells. Moreover, in this narrative review, we aim to discuss other cell organelles targeted by SARS-CoV-2. Lastly, we briefly summarize the studies on various drugs.


Subject(s)
COVID-19 , Cell Membrane/metabolism , Humans , Organelles/metabolism , Peptidyl-Dipeptidase A/metabolism , SARS-CoV-2
4.
Ann N Y Acad Sci ; 1510(1): 79-99, 2022 04.
Article in English | MEDLINE | ID: covidwho-1822055

ABSTRACT

Targeted protein degradation is critical for proper cellular function and development. Protein degradation pathways, such as the ubiquitin proteasomes system, autophagy, and endosome-lysosome pathway, must be tightly regulated to ensure proper elimination of misfolded and aggregated proteins and regulate changing protein levels during cellular differentiation, while ensuring that normal proteins remain unscathed. Protein degradation pathways have also garnered interest as a means to selectively eliminate target proteins that may be difficult to inhibit via other mechanisms. On June 7 and 8, 2021, several experts in protein degradation pathways met virtually for the Keystone eSymposium "Targeting protein degradation: from small molecules to complex organelles." The event brought together researchers working in different protein degradation pathways in an effort to begin to develop a holistic, integrated vision of protein degradation that incorporates all the major pathways to understand how changes in them can lead to disease pathology and, alternatively, how they can be leveraged for novel therapeutics.


Subject(s)
Proteasome Endopeptidase Complex , Ubiquitin , Autophagy/physiology , Humans , Organelles , Proteasome Endopeptidase Complex/metabolism , Proteins/metabolism , Proteolysis , Ubiquitin/metabolism
5.
Nat Commun ; 13(1): 1406, 2022 03 17.
Article in English | MEDLINE | ID: covidwho-1750000

ABSTRACT

Human rhinovirus (HRV), like coronavirus (HCoV), are positive-strand RNA viruses that cause both upper and lower respiratory tract illness, with their replication facilitated by concentrating RNA-synthesizing machinery in intracellular compartments made of modified host membranes, referred to as replication organelles (ROs). Here we report a non-canonical, essential function for stimulator of interferon genes (STING) during HRV infections. While the canonical function of STING is to detect cytosolic DNA and activate inflammatory responses, HRV infection triggers the release of STIM1-bound STING in the ER by lowering Ca2+, thereby allowing STING to interact with phosphatidylinositol 4-phosphate (PI4P) and traffic to ROs to facilitates viral replication and transmission via autophagy. Our results thus hint a critical function of STING in HRV viral replication and transmission, with possible implications for other RO-mediated RNA viruses.


Subject(s)
Enterovirus , RNA Viruses , Humans , Organelles , Rhinovirus , Virus Replication/physiology
6.
Elife ; 102021 12 20.
Article in English | MEDLINE | ID: covidwho-1662832

ABSTRACT

Employing concepts from physics, chemistry and bioengineering, 'learning-by-building' approaches are becoming increasingly popular in the life sciences, especially with researchers who are attempting to engineer cellular life from scratch. The SynCell2020/21 conference brought together researchers from different disciplines to highlight progress in this field, including areas where synthetic cells are having socioeconomic and technological impact. Conference participants also identified the challenges involved in designing, manipulating and creating synthetic cells with hierarchical organization and function. A key conclusion is the need to build an international and interdisciplinary research community through enhanced communication, resource-sharing, and educational initiatives.


Subject(s)
Artificial Cells , Bioengineering/methods , Bioengineering/statistics & numerical data , Bioengineering/trends , Intersectoral Collaboration , Organelles/physiology , Synthetic Biology/trends , Forecasting , Humans
7.
Cells ; 11(1)2021 12 24.
Article in English | MEDLINE | ID: covidwho-1580995

ABSTRACT

The lamellar body (LB) of the alveolar type II (ATII) cell is a lysosome-related organelle (LRO) that contains surfactant, a complex mix of mainly lipids and specific surfactant proteins. The major function of surfactant in the lung is the reduction of surface tension and stabilization of alveoli during respiration. Its lack or deficiency may cause various forms of respiratory distress syndrome (RDS). Surfactant is also part of the innate immune system in the lung, defending the organism against air-borne pathogens. The limiting (organelle) membrane that encloses the LB contains various transporters that are in part responsible for translocating lipids and other organic material into the LB. On the other hand, this membrane contains ion transporters and channels that maintain a specific internal ion composition including the acidic pH of about 5. Furthermore, P2X4 receptors, ligand gated ion channels of the danger signal ATP, are expressed in the limiting LB membrane. They play a role in boosting surfactant secretion and fluid clearance. In this review, we discuss the functions of these transporting pathways of the LB, including possible roles in disease and as therapeutic targets, including viral infections such as SARS-CoV-2.


Subject(s)
COVID-19/metabolism , Ion Channels/metabolism , Lung/metabolism , Membrane Transport Proteins/metabolism , Pulmonary Surfactants/metabolism , COVID-19/virology , Humans , Lung/virology , Organelles/metabolism , Organelles/virology , Pulmonary Alveoli/metabolism , Pulmonary Alveoli/virology , SARS-CoV-2/physiology
8.
PLoS Pathog ; 17(12): e1010113, 2021 12.
Article in English | MEDLINE | ID: covidwho-1553552

ABSTRACT

Emerging coronaviruses (CoVs) pose a severe threat to human and animal health worldwide. To identify host factors required for CoV infection, we used α-CoV transmissible gastroenteritis virus (TGEV) as a model for genome-scale CRISPR knockout (KO) screening. Transmembrane protein 41B (TMEM41B) was found to be a bona fide host factor involved in infection by CoV and three additional virus families. We found that TMEM41B is critical for the internalization and early-stage replication of TGEV. Notably, our results also showed that cells lacking TMEM41B are unable to form the double-membrane vesicles necessary for TGEV replication, indicating that TMEM41B contributes to the formation of CoV replication organelles. Lastly, our data from a mouse infection model showed that the KO of this factor can strongly inhibit viral infection and delay the progression of a CoV disease. Our study revealed that targeting TMEM41B is a highly promising approach for the development of broad-spectrum anti-viral therapeutics.


Subject(s)
CRISPR-Cas Systems , Gastroenteritis, Transmissible, of Swine/virology , Host-Pathogen Interactions , Membrane Proteins/physiology , Organelles/virology , Transmissible gastroenteritis virus/physiology , Virus Replication , Animals , Gastroenteritis, Transmissible, of Swine/genetics , Gastroenteritis, Transmissible, of Swine/transmission , Membrane Proteins/antagonists & inhibitors , Mice , Mice, Inbred C57BL , Swine
9.
Elife ; 102021 08 04.
Article in English | MEDLINE | ID: covidwho-1513060

ABSTRACT

Cilia are hairlike organelles involved in both sensory functions and motility. We discuss the question of whether the location of chemical receptors on cilia provides an advantage in terms of sensitivity and whether motile sensory cilia have a further advantage. Using a simple advection-diffusion model, we compute the capture rates of diffusive molecules on a cilium. Because of its geometry, a non-motile cilium in a quiescent fluid has a capture rate equivalent to a circular absorbing region with ∼4× its surface area. When the cilium is exposed to an external shear flow, the equivalent surface area increases to ∼6×. Alternatively, if the cilium beats in a non-reciprocal way in an otherwise quiescent fluid, its capture rate increases with the beating frequency to the power of 1/3. Altogether, our results show that the protruding geometry of a cilium could be one of the reasons why so many receptors are located on cilia. They also point to the advantage of combining motility with chemical reception.


Subject(s)
Cilia/physiology , Inorganic Chemicals/metabolism , Organic Chemicals/metabolism , Models, Theoretical , Organelles/physiology
10.
Viruses ; 12(10)2020 10 03.
Article in English | MEDLINE | ID: covidwho-1224248

ABSTRACT

Phosphoinositides account for only a small proportion of cellular phospholipids, but have long been known to play an important role in diverse cellular processes, such as cell signaling, the establishment of organelle identity, and the regulation of cytoskeleton and membrane dynamics. As expected, given their pleiotropic regulatory functions, they have key functions in viral replication. The spatial restriction and steady-state levels of each phosphoinositide depend primarily on the concerted action of specific phosphoinositide kinases and phosphatases. This review focuses on a number of remarkable examples of viral strategies involving phosphoinositide kinases to ensure effective viral replication.


Subject(s)
Phosphatidylinositol Phosphates/metabolism , Phosphotransferases (Alcohol Group Acceptor)/metabolism , Virus Diseases/metabolism , Virus Replication/physiology , Animals , Caenorhabditis elegans Proteins , Humans , Organelles/metabolism , Phosphatidylinositols/metabolism , Phosphoric Monoester Hydrolases/metabolism , Phosphotransferases/metabolism , Signal Transduction , Viruses/metabolism
11.
J Mol Cell Biol ; 13(4): 259-268, 2021 08 04.
Article in English | MEDLINE | ID: covidwho-1147985

ABSTRACT

Viruses hijack host functions to invade their target cells and spread to new cells. Specifically, viruses learned to usurp liquid‒liquid phase separation (LLPS), a newly exploited mechanism, used by the cell to concentrate enzymes to accelerate and confine a wide variety of cellular processes. LLPS gives rise to actual membraneless organelles (MLOs), which do not only increase reaction rates but also act as a filter to select molecules to be retained or to be excluded from the liquid droplet. This is exactly what seems to happen with the condensation of SARS-CoV-2 nucleocapsid protein to favor the packaging of intact viral genomes, excluding viral subgenomic or host cellular RNAs. Another older pandemic virus, HIV-1, also takes advantage of LLPS in the host cell during the viral cycle. Recent discoveries highlighted that HIV-1 RNA genome condensates in nuclear MLOs accompanied by specific host and viral proteins, breaking the dogma of retroviruses that limited viral synthesis exclusively to the cytoplasmic compartment. Intriguing fundamental properties of viral/host LLPS remain still unclear. Future studies will contribute to deeply understanding the role of pathogen-induced MLOs in the epidemic invasion of pandemic viruses.


Subject(s)
HIV-1/physiology , Organelles/metabolism , SARS-CoV-2/physiology , COVID-19/pathology , COVID-19/virology , HIV Infections/pathology , HIV Infections/virology , HIV-1/genetics , HIV-1/isolation & purification , Host-Pathogen Interactions , Humans , Nucleocapsid Proteins/metabolism , RNA, Viral/metabolism , SARS-CoV-2/genetics , SARS-CoV-2/isolation & purification , Virus Replication
12.
Cell Microbiol ; 23(8): e13328, 2021 08.
Article in English | MEDLINE | ID: covidwho-1142875

ABSTRACT

Annulate lamellae (AL) have been observed many times over the years on electron micrographs of rapidly dividing cells, but little is known about these unusual organelles consisting of stacked sheets of endoplasmic reticulum-derived membranes with nuclear pore complexes (NPCs). Evidence is growing for a role of AL in viral infection. AL have been observed early in the life cycles of the hepatitis C virus (HCV) and, more recently, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), suggesting a specific induction of mechanisms potentially useful to these pathogens. Like other positive-strand RNA viruses, these viruses induce host cells membranes rearrangements. The NPCs of AL could potentially mediate exchanges between these partially sealed compartments and the cytoplasm. AL may also be involved in regulating Ca2+ homeostasis or cell cycle control. They were recently observed in cells infected with Theileria annulata, an intracellular protozoan parasite inducing cell proliferation. Further studies are required to clarify their role in intracellular pathogen/host-cell interactions.


Subject(s)
Host-Pathogen Interactions/physiology , Organelles/microbiology , Organelles/parasitology , Animals , COVID-19 , Cytoplasm/virology , Endoplasmic Reticulum/microbiology , Endoplasmic Reticulum/parasitology , Endoplasmic Reticulum/ultrastructure , Endoplasmic Reticulum/virology , Humans , Organelles/ultrastructure , Organelles/virology , SARS-CoV-2/physiology
13.
Science ; 369(6509): 1306-1307, 2020 09 11.
Article in English | MEDLINE | ID: covidwho-1007321
14.
Ultrastruct Pathol ; 44(4-6): 519-523, 2020 Nov 20.
Article in English | MEDLINE | ID: covidwho-960391

ABSTRACT

COVID-19 (from SARS-CoV-2) is the cause of an ongoing pandemic, with an increasing number of cases and significant mortality worldwide. Clinical trials and extensive studies are being conducted on a large scale for a better understanding of the pathophysiology of this disease and its effect on different organs. Several experimental treatment protocols have been introduced, in which hydroxychloroquine (HCQ) was one of the first drugs used. While patients can develop many side effects of HCQ, studies have documented a rare association of long-term HCQ treatment with zebra-like bodies in the ultrastructural examination of kidney biopsies, a finding typically seen in Fabry's disease, as well as in association with chronic HCQ use, among other drugs. We present a similar finding in the postmortem examination of a male in his early seventies with COVID-19 infection, who received five days of HCQ treatment before stopping the medication due to cardiac and renal toxicity.


Subject(s)
Acute Kidney Injury/chemically induced , Antiviral Agents/adverse effects , COVID-19/drug therapy , Hydroxychloroquine/adverse effects , Kidney Tubules/drug effects , Organelles/drug effects , Phospholipids/metabolism , Acute Kidney Injury/metabolism , Acute Kidney Injury/pathology , Aged , Autopsy , Fatal Outcome , Humans , Kidney Tubules/metabolism , Kidney Tubules/ultrastructure , Male , Organelles/metabolism , Organelles/ultrastructure
15.
FEBS J ; 288(12): 3799-3812, 2021 06.
Article in English | MEDLINE | ID: covidwho-901043

ABSTRACT

Cells possess a variety of organelles with characteristic structure and subcellular localization intimately linked to their specific function. While most are intracellular and found in virtually all eukaryotic cells, there is a small group of organelles of elongated cylindrical shapes in highly specialized cells that protrude into the extracellular space, such as cilia, flagella, and microvilli. The ATP required by intracellular organelles is amply available in the cytosol, largely generated by mitochondria. However, such is not the case for cilia and flagella, whose slender structures cannot accommodate mitochondria. These organelles consume massive amounts of ATP to carry out high energy-demanding functions, such as sensory transduction or motility. ATP from the nearest mitochondria or other reactions within the cell body is severely limited by diffusion and generally insufficient to fuel the entire length of cilia and flagella. These organelles overcome this fuel restriction by local generation of ATP, using mechanisms that vary depending on the nutrients that are available in their particular external environment. Here, we review, with emphasis in mammals, the remarkable adaptations that cilia and flagella use to fuel their metabolic needs. Additionally, we discuss how a decrease in nutrients surrounding olfactory cilia might impair olfaction in COVID-19 patients.


Subject(s)
Adenosine Triphosphate/metabolism , Cilia/metabolism , Flagella/metabolism , Organelles/metabolism , Animals , COVID-19/metabolism , COVID-19/virology , Humans , Mitochondria/metabolism , Models, Biological , SARS-CoV-2/physiology
16.
Nat Rev Microbiol ; 18(8): 411, 2020 08.
Article in English | MEDLINE | ID: covidwho-606959
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