scholarly journals HIV-1 Hijacking of Host ATPases and GTPases That Control Protein Trafficking

2021 ◽  
Vol 9 ◽  
Author(s):  
Lucas A. Tavares ◽  
Yunan C. Januário ◽  
Luis L. P. daSilva
Keyword(s):  
Host Cell ◽  
Protein Trafficking ◽  
Intracellular Transport ◽  
Host Protein ◽  
Pharmacological Intervention ◽  
Normal Functions ◽  
Associated Proteins ◽  
Viral Components ◽  
Energy Harnessing ◽  
Hiv 1

The human immunodeficiency virus (HIV-1) modifies the host cell environment to ensure efficient and sustained viral replication. Key to these processes is the capacity of the virus to hijack ATPases, GTPases and the associated proteins that control intracellular protein trafficking. The functions of these energy-harnessing enzymes can be seized by HIV-1 to allow the intracellular transport of viral components within the host cell or to change the subcellular distribution of antiviral factors, leading to immune evasion. Here, we summarize how energy-related proteins deviate from their normal functions in host protein trafficking to aid the virus in different phases of its replicative cycle. Recent discoveries regarding the interplay among HIV-1 and host ATPases and GTPases may shed light on potential targets for pharmacological intervention.

scholarly journals HIV-1 Dynamics in the Host Cell: A Review of Viral- and Host- Protein Interactions and Potential Therapeutic Targets for HIV-1 Infection

2016 ◽  
Vol 22 (1) ◽  
pp. 10
Author(s):  
Masha Sorin ◽  
Ganjam V. Kalpana
Keyword(s):  
Viral Replication ◽  
Host Cell ◽  
Nuclear Export ◽  
Host Factors ◽  
Host Protein ◽  
Restriction Factors ◽  
Human Immune System ◽  
Antiviral Responses ◽  
Retroviral Replication ◽  
Hiv 1

HIV-1, the causative agent of AIDS, is a sophisticated retrovirus that has both evolved to invade the complex human immune system and adapted to utilize the host machinery for its own propagation. A dynamic interaction between the virus and host systems can be observed at every step of the HIV-1 lifecycle. Host factors are involved not only in mounting antiviral responses, but are also hijacked by the virus to enhance viral replication. Host factors are necessary for viral replication during entry, reverse transcription, nuclear import, integration, transcription, nuclear export, translation, assembly, and budding. Recently, a new class of host factors, called “host restriction factors,” has been identified that prevent retroviral replication in a specific host cell environment and constitute an important part of intracellular innate immunity against the virus. These restriction factors act as barriers to retroviral replication at various stages within the infected cell. Nevertheless, the HIV-1 virus has learned to subvert these antiviral responses and successfully propagate within the permissive host environment. This review article describes the identification and mechanism of action of several pro- and anti-HIV-1 host factors. It is likely that we are only beginning to get a glimpse of an ongoing complex battle between HIV-1 and the host, the understanding of which should provide valuable information for the development of novel therapeutic strategies against HIV-1. 

scholarly journals HIV-1 Envelope Conformation, Allostery, and Dynamics

Viruses ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 852
Author(s):  
Ashley Lauren Bennett ◽  
Rory Henderson
Keyword(s):  
Host Cell ◽  
Conformational Changes ◽  
Neutralizing Antibodies ◽  
Critical Role ◽  
Cell Receptor ◽  
Broadly Neutralizing Antibodies ◽  
Structural Mapping ◽  
Host Cell Receptor ◽  
Immunogen Design ◽  
Hiv 1

The HIV-1 envelope glycoprotein (Env) mediates host cell fusion and is the primary target for HIV-1 vaccine design. The Env undergoes a series of functionally important conformational rearrangements upon engagement of its host cell receptor, CD4. As the sole target for broadly neutralizing antibodies, our understanding of these transitions plays a critical role in vaccine immunogen design. Here, we review available experimental data interrogating the HIV-1 Env conformation and detail computational efforts aimed at delineating the series of conformational changes connecting these rearrangements. These studies have provided a structural mapping of prefusion closed, open, and transition intermediate structures, the allosteric elements controlling rearrangements, and state-to-state transition dynamics. The combination of these investigations and innovations in molecular modeling set the stage for advanced studies examining rearrangements at greater spatial and temporal resolution.

Interactions Between Salmonella Typhimurium, Enteropathogenic Escherichia Coli (EPEC), and Host Epithelial Cells

1995 ◽  
Vol 9 (1) ◽  
pp. 31-36 ◽  
Author(s):  
B.B. Finlay
Keyword(s):  
Escherichia Coli ◽  
Epithelial Cells ◽  
Salmonella Typhimurium ◽  
Host Cell ◽  
Inositol Phosphate ◽  
Enteric Pathogens ◽  
Host Protein ◽  
Host Cells ◽  
Enteropathogenic Escherichia Coli ◽  
Sequence Of Events

The interactions that occur between pathogenic micro-organisms and their host cells are complex and intimate. We have used two enteric pathogens, Salmonella typhimurium and enteropathogenic Escherichia coli (EPEC), to examine the interactions that occur between these organisms and epithelial cells. Although these are enteric pathogens, the knowledge and techniques developed from these systems may be applied to the study of dental pathogens. Both S. typhimurium and EPEC disrupt epithelial monolayer integrity, although by different mechanisms. Both pathogens cause loss of microvilli and re-arrangement of the underlying host cytoskeleton. Despite these similarities, both organisms send different signals into the host cell. EPEC signal transduction involves generation of intracellular calcium and inositol phosphate fluxes, and activation of host tyrosine kinases that results in tyrosine phosphorylation of a 90-kDa host protein. Bacterial mutants have been identifed that are deficient in signaling to the host. We propose a sequence of events that occur when EPEC interacts with epithelial cells. Once inside a host cell, S. typhimurium remains within a vacuole. To define some of the parameters of the intracellular environment, we constructed genetic fusions of known genes with lacZ, and used these fusions as reporter probes of the intracellular vacuolar environment. We have also begun to examine the bacterial and host cell factors necessary for S. typhimurium to multiply within epithelial cells. We found that this organism triggers the formation of novel tubular lysosomes, and these structures are linked with intracellular replication.

scholarly journals Novel compound inhibitors of HIV-1NL4-3 Vpu

2021 ◽  
Author(s):  
Carolyn A Robinson ◽  
Terri D Lyddon ◽  
Hwi Min Gil ◽  
David T. Evans ◽  
Yury V Kuzmichev ◽  
...  
Keyword(s):  
Host Cell ◽  
Particle Production ◽  
Viral Glycoprotein ◽  
New Class ◽  
Host Cell Proteins ◽  
Viral Particles ◽  
Dependent Cell ◽  
A Cell ◽  
Hiv 1

HIV-1 Vpu targets the host cell proteins CD4 and BST-2/Tetherin for degradation, ultimately resulting in enhanced virus spread and host immune evasion. The discovery and characterization of small molecules that antagonize Vpu would further elucidate the contribution of Vpu to pathogenesis and lay the foundation for the study of a new class of novel HIV-1 therapeutics. To identify novel compounds that block Vpu activity, we developed a cell-based 'gain of function' assay that produces a positive signal in response to Vpu inhibition. To develop this assay, we took advantage of the viral glycoprotein, GaLV Env. In the presence of Vpu, GaLV Env is not incorporated into viral particles, resulting in non-infectious virions. Vpu inhibition restores infectious particle production. Using this assay, a high throughput screen of >650,000 compounds was performed to identify inhibitors that block the biological activity of Vpu. From this screen, we identified several positive hits but focused on two compounds from one structural family, SRI-41897 and SRI-42371. It was conceivable that the compounds inhibited the formation of infectious virions by targeting host cell proteins instead of Vpu directly, so we developed independent counter-screens for off target interactions of the compounds and found no off target interactions. Additionally, these compounds block Vpu-mediated modulation of CD4, BST-2/Tetherin and antibody dependent cell-mediated toxicity (ADCC). Unfortunately, both SRI-41897 and SRI-42371 were shown to be specific to the N-terminal region of NL4-3 Vpu and did not function against other, more clinically relevant, strains of Vpu.

scholarly journals Plasmolipin and Its Role in Cell Processes

2021 ◽  
Vol 55 (6) ◽  
pp. 773-785
Author(s):  
A. A. Shulgin ◽  
T. D. Lebedev ◽  
V. S. Prassolov ◽  
P. V. Spirin
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Intracellular Signaling ◽  
Intracellular Transport ◽  
Virus Entry ◽  
Normal Function ◽  
Normal Functions ◽  
Cell Processes ◽  
Main Component

Abstract The mechanisms involved in the origin and development of malignant and neurodegenerative diseases are an important area of modern biomedicine. A crucial task is to identify new molecular markers that are associated with rearrangements of intracellular signaling and can be used for prognosis and the development of effective treatment approaches. The proteolipid plasmolipin (PLLP) is a possible marker. PLLP is a main component of the myelin sheath and plays an important role in the development and normal function of the nervous system. PLLP is involved in intracellular transport, lipid raft formation, and Notch signaling. PLLP is presumably involved in various disorders, such as cancer, schizophrenia, Alzheimer’s disease, and type 2 diabetes mellitus. PLLP and its homologs were identified as possible virus entry receptors. The review summarizes the data on the PLLP structure, normal functions, and role in diseases.

scholarly journals Phosphoserine acidic cluster motifs in the cytoplasmic domains of transmembrane proteins bind distinct basic regions on the μ subunits of clathrin adaptor protein complexes

2018 ◽  
Author(s):  
Rajendra Singh ◽  
Charlotte Stoneham ◽  
Christopher Lim ◽  
Xiaofei Jia ◽  
Javier Guenaga ◽  
...  
Keyword(s):  
Protein Trafficking ◽  
Transmembrane Proteins ◽  
Adaptor Protein ◽  
Cellular Protein ◽  
Membrane Lipid ◽  
Dependent Manner ◽  
Cytoplasmic Domains ◽  
Clathrin Adaptor ◽  
Hiv 1

AbstractProtein trafficking in the endosomal system involves the recognition of specific signals within the cytoplasmic domains (CDs) of transmembrane proteins by clathrin adaptors. One such signal is the phosphoserine acidic cluster (PSAC), the prototype of which is in the endoprotease Furin. How PSACs are recognized by clathrin adaptors has been controversial. We reported previously that HIV-1 Vpu, which modulates cellular immunoreceptors, contains a PSAC that binds to the µ subunits of clathrin adaptor protein (AP) complexes. Here, we show that the CD of Furin binds the µ subunits of AP-1 and AP-2 in a phosphorylation-dependent manner. Moreover, we identify a PSAC in a cytoplasmic loop of the cellular transmembrane Serinc3, an inhibitor of the infectivity of retroviruses. The two serines within the PSAC of Serinc3 are phosphorylated by casein kinase II and mediate interaction with the µ subunits in vitro. The sites of these serines vary among mammals in a manner consistent with host-pathogen conflict, yet the Serinc3-PSAC seems dispensible for anti-HIV activity and for counteraction by HIV-1 Nef. The CDs of Vpu, Furin, and the PSAC-containing loop of Serinc3 each bind the μ subunit of AP-2 (µ2) with similar affinities, but they appear to utilize different basic regions on µ2. The Serinc3 loop requires a region previously reported to bind the acidic plasma membrane lipid phosphatidylinositol-4,5-bisphosphate. These data suggest that the PSACs within different proteins recognize different basic regions on the µ surface, providing the potential to inhibit the activity of viral proteins without necessarily affecting cellular protein trafficking.

scholarly journals Mathematical model of the Tat-Rev regulation of HIV-1 replication in an activated cell predicts the existence of oscillatory dynamics in the synthesis of viral components

BMC Genomics ◽  
2014 ◽  
Vol 15 (Suppl 12) ◽  
pp. S1 ◽  
Author(s):  
Vitaly A Likhoshvai ◽  
Tamara M Khlebodarova ◽  
Sergei I Bazhan ◽  
Irina A Gainova ◽  
Valery A Chereshnev ◽  
...  
Keyword(s):  
Mathematical Model ◽  
Oscillatory Dynamics ◽  
Viral Components ◽  
Hiv 1

scholarly journals Contrasting Function of Structured N-Terminal and Unstructured C-Terminal Segments of Mycobacterium tuberculosis PPE37 Protein

mBio ◽  
2018 ◽  
Vol 9 (1) ◽  
Author(s):  
Javeed Ahmad ◽  
Aisha Farhana ◽  
Rita Pancsa ◽  
Simran Kaur Arora ◽  
Alagiri Srinivasan ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Mycobacterium Tuberculosis ◽  
Host Cell ◽  
Terminal Segment ◽  
Host Protein ◽  
Host Cells ◽  
Productive Infection ◽  
Disordered Proteins ◽  
Intrinsically Disordered

ABSTRACT Pathogens frequently employ eukaryotic linear motif (ELM)-rich intrinsically disordered proteins (IDPs) to perturb and hijack host cell networks for a productive infection. Mycobacterium tuberculosis has a relatively high percentage of IDPs in its proteome, the significance of which is not known. The Mycobacterium-specific PE-PPE protein family has several members with unusually high levels of structural disorder and disorder-promoting Ala/Gly residues. PPE37 protein, a member of this family, carries an N-terminal PPE domain capable of iron binding, two transmembrane domains, and a disordered C-terminal segment harboring ELMs and a eukaryotic nuclear localization signal (NLS). PPE37, expressed as a function of low iron stress, was cleaved by M. tuberculosis protease into N- and C-terminal segments. A recombinant N-terminal segment (P37N) caused proliferation and differentiation of monocytic THP-1 cells, into CD11c, DC-SIGN (dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin)-positive semimature dendritic cells exhibiting high interleukin-10 (IL-10) but negligible IL-12 and also low tumor necrosis factor alpha (TNF-α) secretion—an environment suitable for maintaining tolerogenic immune cells. The C-terminal segment entered the macrophage nucleus and induced caspase-3-dependent apoptosis of host cells. Mice immunized with recombinant PPE37FL and PPE37N evoked strong anti-inflammatory response, validating the in vitro immunostimulatory effect. Analysis of the IgG response of PPE37FL and PPE37N revealed significant immunoreactivities in different categories of TB patients, viz. pulmonary TB (PTB) and extrapulmonary TB (EPTB), vis-a-vis healthy controls. These results support the role of IDPs in performing contrasting activities to modulate the host processes, possibly through molecular mimicry and cross talk in two spatially distinct host environments which may likely aid M. tuberculosis survival and pathogenesis. IMPORTANCE To hijack the human host cell machinery to enable survival inside macrophages, the pathogen Mycobacterium tuberculosis requires a repertoire of proteins that can mimic host protein function and modulate host cell machinery. Here, we have shown how a single protein can play multiple functions and hijack the host cell for the benefit of the pathogen. Full-length membrane-anchored PPE37 protein is cleaved into N- and C-terminal domains under iron-depleted conditions. The N-terminal domain facilitates the propathogen semimature tolerogenic state of dendritic cells, whereas the C-terminal segment is localized into host cell nucleus and induces apoptosis. The immune implications of these in vitro observations were assessed and validated in mice and also human TB patients. This study presents novel mechanistic insight adopted by M. tuberculosis to survive inside host cells.

Influenza A viruses balance ER stress with host protein synthesis shutoff

2021 ◽  
Vol 118 (36) ◽  
pp. e2024681118
Author(s):  
Beryl Mazel-Sanchez ◽  
Justyna Iwaszkiewicz ◽  
Joao P. P. Bonifacio ◽  
Filo Silva ◽  
Chengyue Niu ◽  
...  
Keyword(s):  
Viral Replication ◽  
Er Stress ◽  
Host Cell ◽  
Messenger Rna ◽  
Influenza A ◽  
Nonstructural Protein ◽  
Host Protein ◽  
Stress Induction ◽  
Nonstructural Protein 1

Excessive production of viral glycoproteins during infections poses a tremendous stress potential on the endoplasmic reticulum (ER) protein folding machinery of the host cell. The host cell balances this by providing more ER resident chaperones and reducing translation. For viruses, this unfolded protein response (UPR) offers the potential to fold more glycoproteins. We postulated that viruses could have developed means to limit the inevitable ER stress to a beneficial level for viral replication. Using a relevant human pathogen, influenza A virus (IAV), we first established the determinant for ER stress and UPR induction during infection. In contrast to a panel of previous reports, we identified neuraminidase to be the determinant for ER stress induction, and not hemagglutinin. IAV relieves ER stress by expression of its nonstructural protein 1 (NS1). NS1 interferes with the host messenger RNA processing factor CPSF30 and suppresses ER stress response factors, such as XBP1. In vivo viral replication is increased when NS1 antagonizes ER stress induction. Our results reveal how IAV optimizes glycoprotein expression by balancing folding capacity.

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