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The REEP5/TRAM1 complex binds SARS-CoV-2 NSP3 and promotes virus replication

Li, Jie; Gui, Qi; Liang, Feng-Xia; Sall, Joseph; Zhang, Qingyue; Duan, Yatong; Dhabaria, Avantika; Askenazi, Manor; Ueberheide, Beatrix; Stapleford, Kenneth A; Pagano, Michele
Generation of virus-host protein-protein interactions (PPIs) maps may provide clues to uncover SARS-CoV-2-hijacked cellular processes. However, these PPIs maps were created by expressing each viral protein singularly, which does not reflect the life situation in which certain viral proteins synergistically interact with host proteins. Our results reveal the host-viral protein-protein interactome of SARS-CoV-2 NSP3, NSP4, and NSP6 expressed individually or in combination. Furthermore, REEP5/TRAM1 complex interacts with NSP3 at ROs and promotes viral replication. The significance of our research is identifying virus-host interactions that may be targeted for therapeutic intervention.
PMCID:10617467
PMID: 37768083
ISSN: 1098-5514
CID: 5614142

A noncanonical function of SKP1 regulates the switch between autophagy and unconventional secretion

Li, Jie; Krause, Gregory J; Gui, Qi; Kaushik, Susmita; Rona, Gergely; Zhang, Qingyue; Liang, Feng-Xia; Dhabaria, Avantika; Anerillas, Carlos; Martindale, Jennifer L; Vasilyev, Nikita; Askenazi, Manor; Ueberheide, Beatrix; Nudler, Evgeny; Gorospe, Myriam; Cuervo, Ana Maria; Pagano, Michele
Intracellular degradation of proteins and organelles by the autophagy-lysosome system is essential for cellular quality control and energy homeostasis. Besides degradation, endolysosomal organelles can fuse with the plasma membrane and contribute to unconventional secretion. Here, we identify a function for mammalian SKP1 in endolysosomes that is independent of its established role as an essential component of the family of SCF/CRL1 ubiquitin ligases. We found that, under nutrient-poor conditions, SKP1 is phosphorylated on Thr131, allowing its interaction with V1 subunits of the vacuolar ATPase (V-ATPase). This event, in turn, promotes V-ATPase assembly to acidify late endosomes and enhance endolysosomal degradation. Under nutrient-rich conditions, SUMOylation of phosphorylated SKP1 allows its binding to and dephosphorylation by the PPM1B phosphatase. Dephosphorylated SKP1 interacts with SEC22B to promote unconventional secretion of the content of less acidified hybrid endosomal/autophagic compartments. Collectively, our study implicates SKP1 phosphorylation as a switch between autophagy and unconventional secretion in a manner dependent on cellular nutrient status.
PMCID:10575587
PMID: 37831778
ISSN: 2375-2548
CID: 5604232

How "rock-and-roll" solved the cullin supply chain problem

Garcia, Sheena Faye; Pagano, Michele
PMID: 37221268
ISSN: 1748-7838
CID: 5543712

A membrane-associated MHC-I inhibitory axis for cancer immune evasion

Chen, Xufeng; Lu, Qiao; Zhou, Hua; Liu, Jia; Nadorp, Bettina; Lasry, Audrey; Sun, Zhengxi; Lai, Baoling; Rona, Gergely; Zhang, Jiangyan; Cammer, Michael; Wang, Kun; Al-Santli, Wafa; Ciantra, Zoe; Guo, Qianjin; You, Jia; Sengupta, Debrup; Boukhris, Ahmad; Zhang, Hongbing; Liu, Cheng; Cresswell, Peter; Dahia, Patricia L M; Pagano, Michele; Aifantis, Iannis; Wang, Jun
Immune-checkpoint blockade has revolutionized cancer treatment, but some cancers, such as acute myeloid leukemia (AML), do not respond or develop resistance. A potential mode of resistance is immune evasion of T cell immunity involving aberrant major histocompatibility complex class I (MHC-I) antigen presentation (AP). To map such mechanisms of resistance, we identified key MHC-I regulators using specific peptide-MHC-I-guided CRISPR-Cas9 screens in AML. The top-ranked negative regulators were surface protein sushi domain containing 6 (SUSD6), transmembrane protein 127 (TMEM127), and the E3 ubiquitin ligase WWP2. SUSD6 is abundantly expressed in AML and multiple solid cancers, and its ablation enhanced MHC-I AP and reduced tumor growth in a CD8+ T cell-dependent manner. Mechanistically, SUSD6 forms a trimolecular complex with TMEM127 and MHC-I, which recruits WWP2 for MHC-I ubiquitination and lysosomal degradation. Together with the SUSD6/TMEM127/WWP2 gene signature, which negatively correlates with cancer survival, our findings define a membrane-associated MHC-I inhibitory axis as a potential therapeutic target for both leukemia and solid cancers.
PMID: 37557169
ISSN: 1097-4172
CID: 5602312

FBXL4 suppresses mitophagy by restricting the accumulation of NIX and BNIP3 mitophagy receptors

Nguyen-Dien, Giang Thanh; Kozul, Keri-Lyn; Cui, Yi; Townsend, Brendan; Kulkarni, Prajakta Gosavi; Ooi, Soo Siang; Marzio, Antonio; Carrodus, Nissa; Zuryn, Steven; Pagano, Michele; Parton, Robert G; Lazarou, Michael; Millard, S Sean; Taylor, Robert W; Collins, Brett M; Jones, Mathew Jk; Pagan, Julia K
To maintain both mitochondrial quality and quantity, cells selectively remove damaged or excessive mitochondria through mitophagy, which is a specialised form of autophagy. Mitophagy is induced in response to diverse conditions, including hypoxia, cellular differentiation and mitochondrial damage. However, the mechanisms that govern the removal of specific dysfunctional mitochondria under steady-state conditions to fine-tune mitochondrial content are not well understood. Here, we report that SCFFBXL4 , an SKP1/CUL1/F-box protein ubiquitin ligase complex, localises to the mitochondrial outer membrane in unstressed cells and mediates the constitutive ubiquitylation and degradation of the mitophagy receptors NIX and BNIP3 to suppress basal levels of mitophagy. We demonstrate that the pathogenic variants of FBXL4 that cause encephalopathic mtDNA depletion syndrome (MTDPS13) do not efficiently interact with the core SCF ubiquitin ligase machinery or mediate the degradation of NIX and BNIP3. Thus, we reveal a molecular mechanism whereby FBXL4 actively suppresses mitophagy by preventing NIX and BNIP3 accumulation. We propose that the dysregulation of NIX and BNIP3 turnover causes excessive basal mitophagy in FBXL4-associated mtDNA depletion syndrome.
PMID: 37161784
ISSN: 1460-2075
CID: 5538212

Apoptotic cell death in disease-Current understanding of the NCCD 2023

Vitale, Ilio; Pietrocola, Federico; Guilbaud, Emma; Aaronson, Stuart A; Abrams, John M; Adam, Dieter; Agostini, Massimiliano; Agostinis, Patrizia; Alnemri, Emad S; Altucci, Lucia; Amelio, Ivano; Andrews, David W; Aqeilan, Rami I; Arama, Eli; Baehrecke, Eric H; Balachandran, Siddharth; Bano, Daniele; Barlev, Nickolai A; Bartek, Jiri; Bazan, Nicolas G; Becker, Christoph; Bernassola, Francesca; Bertrand, Mathieu J M; Bianchi, Marco E; Blagosklonny, Mikhail V; Blander, J Magarian; Blandino, Giovanni; Blomgren, Klas; Borner, Christoph; Bortner, Carl D; Bove, Pierluigi; Boya, Patricia; Brenner, Catherine; Broz, Petr; Brunner, Thomas; Damgaard, Rune Busk; Calin, George A; Campanella, Michelangelo; Candi, Eleonora; Carbone, Michele; Carmona-Gutierrez, Didac; Cecconi, Francesco; Chan, Francis K-M; Chen, Guo-Qiang; Chen, Quan; Chen, Youhai H; Cheng, Emily H; Chipuk, Jerry E; Cidlowski, John A; Ciechanover, Aaron; Ciliberto, Gennaro; Conrad, Marcus; Cubillos-Ruiz, Juan R; Czabotar, Peter E; D'Angiolella, Vincenzo; Daugaard, Mads; Dawson, Ted M; Dawson, Valina L; De Maria, Ruggero; De Strooper, Bart; Debatin, Klaus-Michael; Deberardinis, Ralph J; Degterev, Alexei; Del Sal, Giannino; Deshmukh, Mohanish; Di Virgilio, Francesco; Diederich, Marc; Dixon, Scott J; Dynlacht, Brian D; El-Deiry, Wafik S; Elrod, John W; Engeland, Kurt; Fimia, Gian Maria; Galassi, Claudia; Ganini, Carlo; Garcia-Saez, Ana J; Garg, Abhishek D; Garrido, Carmen; Gavathiotis, Evripidis; Gerlic, Motti; Ghosh, Sourav; Green, Douglas R; Greene, Lloyd A; Gronemeyer, Hinrich; Häcker, Georg; Hajnóczky, György; Hardwick, J Marie; Haupt, Ygal; He, Sudan; Heery, David M; Hengartner, Michael O; Hetz, Claudio; Hildeman, David A; Ichijo, Hidenori; Inoue, Satoshi; Jäättelä, Marja; Janic, Ana; Joseph, Bertrand; Jost, Philipp J; Kanneganti, Thirumala-Devi; Karin, Michael; Kashkar, Hamid; Kaufmann, Thomas; Kelly, Gemma L; Kepp, Oliver; Kimchi, Adi; Kitsis, Richard N; Klionsky, Daniel J; Kluck, Ruth; Krysko, Dmitri V; Kulms, Dagmar; Kumar, Sharad; Lavandero, Sergio; Lavrik, Inna N; Lemasters, John J; Liccardi, Gianmaria; Linkermann, Andreas; Lipton, Stuart A; Lockshin, Richard A; López-Otín, Carlos; Luedde, Tom; MacFarlane, Marion; Madeo, Frank; Malorni, Walter; Manic, Gwenola; Mantovani, Roberto; Marchi, Saverio; Marine, Jean-Christophe; Martin, Seamus J; Martinou, Jean-Claude; Mastroberardino, Pier G; Medema, Jan Paul; Mehlen, Patrick; Meier, Pascal; Melino, Gerry; Melino, Sonia; Miao, Edward A; Moll, Ute M; Muñoz-Pinedo, Cristina; Murphy, Daniel J; Niklison-Chirou, Maria Victoria; Novelli, Flavia; Núñez, Gabriel; Oberst, Andrew; Ofengeim, Dimitry; Opferman, Joseph T; Oren, Moshe; Pagano, Michele; Panaretakis, Theocharis; Pasparakis, Manolis; Penninger, Josef M; Pentimalli, Francesca; Pereira, David M; Pervaiz, Shazib; Peter, Marcus E; Pinton, Paolo; Porta, Giovanni; Prehn, Jochen H M; Puthalakath, Hamsa; Rabinovich, Gabriel A; Rajalingam, Krishnaraj; Ravichandran, Kodi S; Rehm, Markus; Ricci, Jean-Ehrland; Rizzuto, Rosario; Robinson, Nirmal; Rodrigues, Cecilia M P; Rotblat, Barak; Rothlin, Carla V; Rubinsztein, David C; Rudel, Thomas; Rufini, Alessandro; Ryan, Kevin M; Sarosiek, Kristopher A; Sawa, Akira; Sayan, Emre; Schroder, Kate; Scorrano, Luca; Sesti, Federico; Shao, Feng; Shi, Yufang; Sica, Giuseppe S; Silke, John; Simon, Hans-Uwe; Sistigu, Antonella; Stephanou, Anastasis; Stockwell, Brent R; Strapazzon, Flavie; Strasser, Andreas; Sun, Liming; Sun, Erwei; Sun, Qiang; Szabadkai, Gyorgy; Tait, Stephen W G; Tang, Daolin; Tavernarakis, Nektarios; Troy, Carol M; Turk, Boris; Urbano, Nicoletta; Vandenabeele, Peter; Vanden Berghe, Tom; Vander Heiden, Matthew G; Vanderluit, Jacqueline L; Verkhratsky, Alexei; Villunger, Andreas; von Karstedt, Silvia; Voss, Anne K; Vousden, Karen H; Vucic, Domagoj; Vuri, Daniela; Wagner, Erwin F; Walczak, Henning; Wallach, David; Wang, Ruoning; Wang, Ying; Weber, Achim; Wood, Will; Yamazaki, Takahiro; Yang, Huang-Tian; Zakeri, Zahra; Zawacka-Pankau, Joanna E; Zhang, Lin; Zhang, Haibing; Zhivotovsky, Boris; Zhou, Wenzhao; Piacentini, Mauro; Kroemer, Guido; Galluzzi, Lorenzo
Apoptosis is a form of regulated cell death (RCD) that involves proteases of the caspase family. Pharmacological and genetic strategies that experimentally inhibit or delay apoptosis in mammalian systems have elucidated the key contribution of this process not only to (post-)embryonic development and adult tissue homeostasis, but also to the etiology of multiple human disorders. Consistent with this notion, while defects in the molecular machinery for apoptotic cell death impair organismal development and promote oncogenesis, the unwarranted activation of apoptosis promotes cell loss and tissue damage in the context of various neurological, cardiovascular, renal, hepatic, infectious, neoplastic and inflammatory conditions. Here, the Nomenclature Committee on Cell Death (NCCD) gathered to critically summarize an abundant pre-clinical literature mechanistically linking the core apoptotic apparatus to organismal homeostasis in the context of disease.
PMCID:10130819
PMID: 37100955
ISSN: 1476-5403
CID: 5465212

CDT1, a licensing factor that limits rereplication

Rona, Gergely; Pagano, Michele
Cells must avoid licensing of neosynthesized DNA to prevent rereplication. In this issue of Molecular Cell, Ratnayeke et al. (2022)1 reveal how the licensing factor CDT1, prior to its degradation, inhibits DNA elongation by suppressing CMG helicase progression at replication forks.
PMID: 36608666
ISSN: 1097-4164
CID: 5410172

Extracellular matrix stiffness regulates degradation of MST2 via SCF βTrCP

Fiore, Ana Paula Zen Petisco; Rodrigues, Ana Maria; Ribeiro-Filho, Helder Veras; Manucci, Antonio Carlos; de Freitas Ribeiro, Pedro; Botelho, Mayara Carolinne Silva; Vogel, Christine; Lopes-de-Oliveira, Paulo Sergio; Pagano, Michele; Bruni-Cardoso, Alexandre
The Hippo pathway plays central roles in relaying mechanical signals during development and tumorigenesis, but how the proteostasis of the Hippo kinase MST2 is regulated remains unknown. Here, we found that chemical inhibition of proteasomal proteolysis resulted in increased levels of MST2 in human breast epithelial cells. MST2 binds SCFβTrCP E3 ubiquitin ligase and silencing βTrCP resulted in MST2 accumulation. Site-directed mutagenesis combined with computational molecular dynamics studies revealed that βTrCP binds MST2 via a non-canonical degradation motif. Additionally, stiffer extracellular matrix, as well as hyperactivation of integrins resulted in enhanced MST2 degradation mediated by integrin-linked kinase (ILK) and actomyosin stress fibers. Our study uncovers the underlying biochemical mechanisms controlling MST2 degradation and underscores how alterations in the microenvironment rigidity regulate the proteostasis of a central Hippo pathway component.
PMID: 36044955
ISSN: 1872-8006
CID: 5332142

The NSP14/NSP10 RNA repair complex as a Pan-coronavirus therapeutic target

Rona, Gergely; Zeke, Andras; Miwatani-Minter, Bearach; de Vries, Maren; Kaur, Ramanjit; Schinlever, Austin; Garcia, Sheena Faye; Goldberg, Hailey V; Wang, Hui; Hinds, Thomas R; Bailly, Fabrice; Zheng, Ning; Cotelle, Philippe; Desmaële, Didier; Landau, Nathaniel R; Dittmann, Meike; Pagano, Michele
The risk of zoonotic coronavirus spillover into the human population, as highlighted by the SARS-CoV-2 pandemic, demands the development of pan-coronavirus antivirals. The efficacy of existing antiviral ribonucleoside/ribonucleotide analogs, such as remdesivir, is decreased by the viral proofreading exonuclease NSP14-NSP10 complex. Here, using a novel assay and in silico modeling and screening, we identified NSP14-NSP10 inhibitors that increase remdesivir's potency. A model compound, sofalcone, both inhibits the exonuclease activity of SARS-CoV-2, SARS-CoV, and MERS-CoV in vitro, and synergistically enhances the antiviral effect of remdesivir, suppressing the replication of SARS-CoV-2 and the related human coronavirus OC43. The validation of top hits from our primary screenings using cellular systems provides proof-of-concept for the NSP14 complex as a therapeutic target.
PMCID:8640510
PMID: 34862481
ISSN: 1476-5403
CID: 5069282

EMSY inhibits homologous recombination repair and the interferon response, promoting lung cancer immune evasion

Marzio, Antonio; Kurz, Emma; Sahni, Jennifer M; Di Feo, Giuseppe; Puccini, Joseph; Jiang, Shaowen; Hirsch, Carolina Alcantara; Arbini, Arnaldo A; Wu, Warren L; Pass, Harvey I; Bar-Sagi, Dafna; Papagiannakopoulos, Thales; Pagano, Michele
Non-small cell lung cancers (NSCLCs) harboring KEAP1 mutations are often resistant to immunotherapy. Here, we show that KEAP1 targets EMSY for ubiquitin-mediated degradation to regulate homologous recombination repair (HRR) and anti-tumor immunity. Loss of KEAP1 in NSCLC induces stabilization of EMSY, producing a BRCAness phenotype, i.e., HRR defects and sensitivity to PARP inhibitors. Defective HRR contributes to a high tumor mutational burden that, in turn, is expected to prompt an innate immune response. Notably, EMSY accumulation suppresses the type I interferon response and impairs innate immune signaling, fostering cancer immune evasion. Activation of the type I interferon response in the tumor microenvironment using a STING agonist results in the engagement of innate and adaptive immune signaling and impairs the growth of KEAP1-mutant tumors. Our results suggest that targeting PARP and STING pathways, individually or in combination, represents a therapeutic strategy in NSCLC patients harboring alterations in KEAP1.
PMID: 34963055
ISSN: 1097-4172
CID: 5108142