Article
Virology
Mitchell J. Mumby, Aaron L. Johnson, Steven M. Trothen, Cassandra R. Edgar, Richard Gibson, Peter B. Stathopulos, Eric J. Arts, Jimmy D. Dikeakos
Summary: Research has shown that Nef isolates from acutely HIV-1 infected women in Zimbabwe (2410 and 2391 Nef) have similar effects on CD4 receptor downregulation, but only 2410 Nef has the ability to downregulate SERINC5. Mutations in the dileucine motif of 2410 Nef affect its ability to downregulate both SERINC5 and CD4, and HIV-1 infections with 2410 Nef are associated with CD4(+) T cell decline and disease progression.
JOURNAL OF VIROLOGY
(2021)
Article
Cell Biology
Sergio Castro-Gonzalez, Yuhang Shi, Marta Colomer-Lluch, Ying Song, Kaitlyn Mowery, Sharilyn Almodovar, Anju Bansal, Frank Kirchhoff, Konstantin Sparrer, Chengyu Liang, Ruth Serra-Moreno
Summary: Macroautophagy/autophagy is an innate antiviral defense mechanism that targets virions and viral components for degradation, but its role in HIV infection is unclear. Studies show that autophagy poses a hurdle for HIV replication, but HIV-1 uses Nef to counteract this restriction.
Review
Immunology
Lucia Cano-Ortiz, Tom Luedde, Carsten Muenk
Summary: SER5 is a transmembrane protein that has the ability to inhibit the entry of HIV-1 by disrupting viral fusion with the host cell membrane. It is also involved in innate signaling pathways and plays a role in the induction of inflammatory cytokines.
MEDICAL MICROBIOLOGY AND IMMUNOLOGY
(2023)
Review
Virology
Lori A. Emert-Sedlak, Haibin Shi, Colin M. Tice, Li Chen, John J. Alvarado, Sherry T. Shu, Shoucheng Du, Catherine E. Thomas, Jay E. Wrobel, Allen B. Reitz, Thomas E. Smithgall
Summary: This review focuses on the discovery of pharmacological inhibitors of the HIV-1 Nef accessory protein. Nef inhibitors not only suppress HIV-1 replication, but also restore sufficient MHC-I to the surface of infected cells to trigger a cytotoxic T lymphocyte response. Combining Nef inhibitors with other therapeutic approaches may provide a path to clearing viral reservoirs.
Article
Infectious Diseases
Susanna L. Lamers, Gary B. Fogel, Enoch S. Liu, David J. Nolan, Rebecca Rose, Michael S. McGrath
Summary: This study analyzed Nef sequences from different HIV subtypes using a machine learning approach and identified unique physicochemical features associated with subtype-specific Nef functional/structural domains. The results showed that each subtype had specific physicochemical features in Nef protein domains, supporting the hypothesis that varied Nef subtypes contribute to subtype-specific disease progression.
INFECTION GENETICS AND EVOLUTION
(2023)
Article
Virology
Virginia Pierini, Lara Gallucci, Christina M. Stuerzel, Frank Kirchhoff, Oliver T. Fackler
Summary: This study investigates the impact of host cell restriction factors on HIV-1 replication, revealing that S5 exhibits varying antiviral effects on different types of HIV target cells, which can be antagonized by Nef. The results highlight the importance of studying RF function in the context of cell type and donor variabilities.
JOURNAL OF VIROLOGY
(2021)
Article
Virology
Claudia Firrito, Cinzia Bertelli, Annachiara Rosa, Ajit Chande, Swetha Ananth, Hannah van Dijk, Oliver T. Fackler, Charlotte Stoneham, Rajendra Singh, John Guatelli, Massimo Pizzato
Summary: The host protein SERINC5 is incorporated into retrovirus particles and inhibits HIV-1 infectivity. The viral protein Nef counteracts SERINC5 by downregulating it and preventing its incorporation into virions. The ability of Nef to counteract SERINC5 varies between HIV-1 isolates. The study identified a specific Nef allele that is unable to counteract SERINC5 and investigated the molecular determinants responsible for this defect. A specific amino acid substitution was found to restore the ability of the defective Nef to counteract SERINC5 and promote HIV-1 infectivity.
Article
Biochemistry & Molecular Biology
Alexei A. Adzhubei, Amol Kulkarni, Anna P. Tolstova, Anastasia A. Anashkina, Dmitri Sviridov, Alexander A. Makarov, Michael I. Bukrinsky
Summary: HIV-1 infection impairs cellular cholesterol efflux through downregulation of the cholesterol transporter ABCA1, with potential implications for metabolic co-morbidities. Inhibitors targeting the Nef:ABCA1 interaction may offer a promising approach to attenuate HIV-associated co-morbidities.
COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL
(2021)
Article
Virology
Zita Kruize, Ad C. van Nuenen, Stan W. van Wijk, Arginell F. Girigorie, Karel A. van Dort, Thijs Booiman, Neeltje A. Kootstra
Summary: This study examined the impact of naturally occurring mutations in HIV-1 Nef on its ability to counteract SERINC restriction and disease progression in infection. The results showed that mutations in Nef affect the ability of Nef to counteract SERINC3 and SERINC5, with certain mutations associated with increased or decreased infectivity and disease progression.
Article
Immunology
Maria Ghaly, Jessica Proulx, Kathleen Borgmann, In-Woo Park
Summary: Our recent data reveal that HIV-1 Nef plays a crucial role in determining the fate of cellular proteins by modulating ubiquitination. Through proteomic analysis, we identified 93 proteins upregulated and 232 proteins downregulated in ubiquitination status by Nef. These proteins were classified based on molecular function, biological process, subcellular localization, and biological pathway. Among the ubiquitinated proteins, six directly interacted with Nef, and 14 were involved in protein stability through the Ubiquitin Proteasome System (UPS)-mediated proteasomal degradation pathway. The molecular mechanisms underlying Nef-triggered regulation of cellular protein ubiquitination are currently being investigated.
FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY
(2023)
Article
Cell Biology
Geremy Sannier, Mathieu Dube, Caroline Dufour, Corentin Richard, Nathalie Brassard, Gloria-Gabrielle Delgado, Amelie Pagliuzza, Amy E. Baxter, Julia Niessl, Elsa Brunet-Ratnasingham, Roxanne Charlebois, Bertrand Routy, Jean-Pierre Routy, Remi Fromentin, Nicolas Chomont, Daniel E. Kaufmann
Summary: Understanding the diversity of HIV-1 reservoirs is crucial for a cure, but studying them at the single-cell level in primary samples is challenging. Different viral gene expression and translation patterns are observed in viremic and ART-suppressed individuals, with most reactivated proviruses found to be defective. LRAs induce a wide variety of viral gene transcription and translation patterns, with different effects on various memory cell subsets.
Article
Biophysics
Arpa Hudait, James H. Hurley, Gregory A. Voth
Summary: In the late stages of the HIV-1 life cycle, the membrane localization and self-assembly of Gag polyproteins induce membrane deformation and budding. The release of the virion requires the interaction between Gag lattice and ESCRT machinery at the viral budding site, followed by the assembly of downstream ESCRT-III factors. However, the molecular details of upstream ESCRT assembly dynamics remain unclear. In this study, molecular simulations were used to investigate the interactions between Gag, ESCRT-I, ESCRT-II, and membrane, revealing the mechanisms by which upstream ESCRTs assemble at the viral budding site.
BIOPHYSICAL JOURNAL
(2023)
Article
Multidisciplinary Sciences
Li Zhao, Shumei Wang, Meng Xu, Yang He, Xiaowei Zhang, Ying Xiong, Hong Sun, Haibo Ding, Wenqing Geng, Hong Shang, Guoxin Liang
Summary: In this study, researchers demonstrate that the HIV accessory protein Vpr mediates the degradation of host lysosomal-associated transmembrane protein 5 (LAPTM5) in monocyte-derived macrophages (MDM) to enhance infection in macrophages, potentially providing a strategy for anti-HIV/AIDS therapeutics.
NATURE COMMUNICATIONS
(2021)
Article
Neurosciences
Martina Donadoni, Wenfei Huang, Shadan S. Yarandi, Tricia H. Burdo, Sulie L. Chang, Ilker K. Sariyer
Summary: This study investigated the molecular impact of morphine and HIV-1 on the regulation of OPRM1 pre-mRNA splicing, showing that morphine specifically induces alternative splicing of the MOR-1X isoform in neuronal cells, and HIV-1 may alter MOR isoform expression, particularly with the Nef protein amplifying the rate of MOR-1X alternative splicing induced by morphine.
JOURNAL OF NEUROIMMUNE PHARMACOLOGY
(2022)
Article
Multidisciplinary Sciences
Viviana Cobos Jimenez, Aviva Geretz, Andrey Tokarev, Philip K. Ehrenberg, Selase Deletsu, Kawthar Machmach, Prakriti Mudvari, J. Natalie Howard, Amanda Zelkoski, Dominic Paquin-Proulx, Gregory Q. Del Prete, Caroline Subra, Eli A. Boritz, Alberto Bosque, Rasmi Thomas, Diane L. Bolton
Summary: AP-1 transcription factor plays an important role in latent HIV-1 infection and reactivation. Inhibiting AP-1 may be a potential therapeutic approach to limit HIV-1 reservoirs.
Article
Biochemistry & Molecular Biology
Roua Hassoun, Constanze Erdmann, Sebastian Schmitt, Setsuko Fujita-Becker, Andreas Muegge, Rasmus R. Schroeder, Matthias Geyer, Mina Borbor, Kornelia Jaquet, Nazha Hamdani, Hans Georg Mannherz
Summary: Expression of cardiac alpha-actin and its mutants using the insect cell system revealed differences in filament length and morphology, as well as varying Ca2+-sensitivity of myosin-S1 ATPase stimulation. The addition of cardiac tropomyosin and troponin affected the enzyme activity differently in wild type and mutant actins. Overall, hypertrophic and dilated cardiomyopathy-related mutants showed distinct responses to Ca2+-sensitivity compared to the wild type.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Multidisciplinary Sciences
Annemarie Steiner, Katja Hrovat-Schaale, Ignazia Prigione, Chien-Hsiung Yu, Pawat Laohamonthonkul, Cassandra R. Harapas, Ronnie Ren Jie Low, Dominic De Nardo, Laura F. Dagley, Michael J. Mlodzianoski, Kelly L. Rogers, Thomas Zillinger, Gunther Hartmann, Michael P. Gantier, Marco Gattorno, Matthias Geyer, Stefano Volpi, Sophia Davidson, Seth L. Masters
Summary: Deficiency in COPI complex I may lead to aberrant activation of the STING pathway and inflammatory diseases, with cGAS possibly being the upstream immune sensor driving this process. Targeted inhibition of the cGAS/STING pathway can alleviate inflammation in diseases such as COPA syndrome.
NATURE COMMUNICATIONS
(2022)
Article
Biochemistry & Molecular Biology
Robert Duester, Yanlong Ji, Kuan-Ting Pan, Henning Urlaub, Matthias Geyer
Summary: In this study, the substrate specificity and function of Cdk10 were thoroughly analyzed, revealing its important role in cell cycle regulation and transcriptional regulation. Cdk10 can act as a tumor suppressor and potentially interact with other CDKs.
Article
Multidisciplinary Sciences
Inga Hochheiser, Heide Behrmann, Gregor Hagelueken, Juan F. Rodriguez-Alcazar, Anja Kopp, Eicke Latz, Elmar Behrmann, Matthias Geyer
Summary: In this study, the cryo-EM structure of the human NLRP3(PYD) filament was determined, and a characteristic structure of the filament ends was identified. It was found that the ASC adaptor protein only interacts with the B-end of the filament. A molecular model of the ASC speck consisting of active NLRP3, ASC, and Caspase-1 proteins was proposed.
Article
Oncology
Kai Funke, Robert Duster, Prince De-Graft Wilson, Lena Arevalo, Matthias Geyer, Hubert Schorle
Summary: Transcriptional cyclin-dependent kinase inhibitors have shown high cytotoxicity on certain testicular germ cell tumor cell lines, suggesting a promising alternative treatment option for type II testicular germ cell tumors.
Article
Biochemistry & Molecular Biology
Marina N. N. Iriondo, Asier Etxaniz, Yaiza R. R. Varela, Uxue Ballesteros, Melisa Lazaro, Mikel Valle, Dorotea Fracchiolla, Sascha Martens, L. Ruth Montes, Felix M. Goni, Alicia Alonso
Summary: In macroautophagy, the ATG12-ATG5-ATG16L1 or E3-like complex plays a crucial role in AP formation by promoting LC3/GABARAP proteins anchoring to the AP membrane. However, E3 inhibits LC3/GABARAP capacity to induce inter-vesicular lipid mixing or subsequent fusion. Our results suggest a model of AP expansion in which the LC3/GABARAP proteins involved should be susceptible to lipidation in the absence of E3, or else a regulatory mechanism would allow vesicle incorporation and phagophore growth when E3 is present.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2023)
Review
Biochemistry & Molecular Biology
Elias Adriaenssens, Luca Ferrari, Sascha Martens
Summary: Selective autophagy is a crucial pathway for the removal of damaged material in cells and plays a key role in various neurodegenerative diseases. Cargo receptors act as multitasking tools in selective autophagy by recognizing cargo, recruiting autophagosome biogenesis machinery, and aligning membranes with cargo. Understanding the mechanisms of action of cargo receptors in the degradation of misfolded, ubiquitinated proteins, and damaged mitochondria can guide the development of future therapies.
Article
Multidisciplinary Sciences
Liv E. Jensen, Shanlin Rao, Martina Schuschnig, A. King Cada, Sascha Martens, Gerhard Hummer, James H. Hurley
Summary: Research shows that the ATG12-ATG5-ATG16L1 complex has a strong affinity for highly curved membranes during autophagy initiation, and can increase membrane curvature and facilitate autophagosome growth.
Article
Cell Biology
Bernd Bauer, Sascha Martens, Luca Ferrari
Summary: Cells maintain the functionality of their proteome through the proteostasis network, which includes chaperones, the ubiquitin-proteasome system, and autophagy. The decline of this network leads to protein aggregate accumulation and is associated with aging and disease. This article provides an overview of the molecular mechanisms of aggrephagy, a selective autophagy pathway for protein aggregate removal, including its regulation through post-translational modifications and auxiliary proteins. It also discusses alternative aggrephagy pathways in physiology and their disruption in pathology, particularly focusing on aggrephagy in neurons and protein aggregation in various diseases. Finally, strategies to reprogram aggrephagy for the treatment of protein aggregation diseases are highlighted.
JOURNAL OF CELL SCIENCE
(2023)
Article
Biochemistry & Molecular Biology
Thanh Ngoc Nguyen, Justyna Sawa-Makarska, Grace Khuu, Wai Kit Lam, Elias Adriaenssens, Dorotea Fracchiolla, Stephen Shoebridge, Daniel Bernklau, Benjamin Scott Padman, Marvin Skulsuppaisarn, Runa S. J. Lindblom, Sascha Martens, Michael Lazarou
Summary: Cargo sequestration is a fundamental step of selective autophagy, where cells generate a double-membrane structure called an autophagosome on the surface of cargoes. The initiation of autophagosome formation during selective autophagy by the OPTN protein remains unknown. This study reveals an unconventional path of PINK1/Parkin mitophagy initiation by OPTN that utilizes the kinase TBK1 to initiate mitophagy, which is functionally redundant with ULK1/2 during NDP52 mitophagy initiation.
Article
Biology
Lisa Goebel, Tonia Kirschner, Sandra Koska, Amrita Rai, Petra Janning, Stefano Maffini, Helge Vatheuer, Paul Czodrowski, Roger S. Goody, Matthias P. Mueller, Daniel Rauh
Summary: In this study, we developed nucleotide-based covalent inhibitors for the oncogenic mutant KRasG13C, which has been difficult to target in the past. These inhibitors showed promising properties and successfully locked KRasG13C in a crystal structure. Importantly, the modified KRasG13C protein with these inhibitors was unable to undergo nucleotide exchange and induce oncogenic signaling in cells, suggesting the potential use of nucleotide-based inhibitors for KRasG13C-driven cancer.
Article
Cell Biology
Thomas A. Leonard, Martin Loose, Sascha Martens
Summary: Membranes are essential for life as they define cells and organelles as semi-permeable boundaries. They not only confine proteins and align reaction partners, but also directly control enzymatic activities in biochemical reaction networks. Membrane-localized reactions shape cellular membranes, compartmentalize processes, and create signaling gradients.
DEVELOPMENTAL CELL
(2023)
Article
Biochemistry & Molecular Biology
Keith B. Boyle, Cara J. Ellison, Paul R. Elliott, Martina Schuschnig, Krista Grimes, Marc S. Dionne, Chihiro Sasakawa, Sean Munro, Sascha Martens, Felix Randow
Summary: Invasive bacteria can enter host cells and expose danger signals such as glycans and sphingomyelin to the cytosol through the rupture of bacteria-containing vacuoles. The receptor TECPR1 is identified as responsible for sensing and responding to cytosolically exposed sphingomyelin by recruiting ATG5 to mediate lipid conjugation of LC3. The specificity of the ATG5/ATG12-E3 ligase is conferred by interchangeable receptor subunits, ATG16L1 and TECPR1, resembling certain multi-subunit ubiquitin E3 ligases.
Article
Biochemistry & Molecular Biology
Olivia Harding, Elisabeth Holzer, Julia F. Riley, Sascha Martens, Erika L. F. Holzbaur
Summary: Failure to remove damaged mitochondria through mitophagy can disrupt physiological function and initiate damage signaling through inflammatory cascades. We found that NEMO is recruited to damaged mitochondria in a Parkin-dependent manner, leading to the activation of NF-kB signaling and upregulation of inflammatory cytokines. NEMO is also recruited to mitochondria in primary astrocytes under oxidative stress.
Article
Biology
Riccardo Trapannone, Julia Romanov, Sascha Martens
Summary: Accumulation of protein aggregates is a common feature of neurodegenerative diseases. The cargo receptors p62 and NBR1 play crucial roles in the selective autophagy of protein aggregates. They bind ubiquitinated cargo material and tether it to autophagic membranes.
LIFE SCIENCE ALLIANCE
(2023)