Yan Zhen

• Zhen, Yan & Stenmark, Harald Alfred (2025). Sustained release of cytokines from migrasomes. Extracellular Vesicles and Circulating Nucleic Acids (EVCNA). 6, s. 171–175. doi: 10.20517/evcna.2025.15. Fulltekst i vitenarkiv Vis sammendrag

  Cytokines are released by cells in response to infections and tissue damage. A recent paper by Jiao et al. demonstrates that circulating monocytes release the cytokines tumor necrosis factor and Interleukin-6 encapsulated in large extracellular vesicles called migrasomes, from which the cytokines are secreted locally in a sustained fashion.

• Zhen, Yan & Stenmark, Harald Alfred (2024). A dual-purpose fusion complex in autophagy. Cell Research. ISSN 1001-0602. doi: 10.1038/s41422-023-00925-w. Fulltekst i vitenarkiv
• Zhen, Yan & Stenmark, Harald Alfred (2024). Exosome regulation by Rubicon in ageing. Nature Cell Biology. ISSN 1465-7392. 26, s. 1380–1381. doi: 10.1038/s41556-024-01482-z. Fulltekst i vitenarkiv
• Brugger, Melanie; Lauri, Antonella; Zhen, Yan; Gramegna, Laura L.; Zott, Benedikt & Sekulic, Nikolina [Vis alle 40 forfattere av denne artikkelen] (2024). Bi-allelic variants in SNF8 cause a disease spectrum ranging from severe developmental and epileptic encephalopathy to syndromic optic atrophy. American Journal of Human Genetics. ISSN 0002-9297. 111(3), s. 594–613. doi: 10.1016/j.ajhg.2024.02.005. Fulltekst i vitenarkiv Vis sammendrag

  The endosomal sorting complex required for transport (ESCRT) machinery is essential for membrane remodeling and autophagy and it comprises three multi-subunit complexes (ESCRT I-III). We report nine individuals from six families presenting with a spectrum of neurodevelopmental/neurodegenerative features caused by bi-allelic variants in SNF8 (GenBank: NM_007241.4), encoding the ESCRT-II subunit SNF8. The phenotypic spectrum included four individuals with severe developmental and epileptic encephalopathy, massive reduction of white matter, hypo-/aplasia of the corpus callosum, neurodevelopmental arrest, and early death. A second cohort shows a milder phenotype with intellectual disability, childhood-onset optic atrophy, or ataxia. All mildly affected individuals shared the same hypomorphic variant, c.304G>A (p.Val102Ile). In patient-derived fibroblasts, bi-allelic SNF8 variants cause loss of ESCRT-II subunits. Snf8 loss of function in zebrafish results in global developmental delay and altered embryo morphology, impaired optic nerve development, and reduced forebrain size. In vivo experiments corroborated the pathogenicity of the tested SNF8 variants and their variable impact on embryo development, validating the observed clinical heterogeneity. Taken together, we conclude that loss of ESCRT-II due to bi-allelic SNF8 variants is associated with a spectrum of neurodevelopmental/neurodegenerative phenotypes mediated likely via impairment of the autophagic flux.

• Zhen, Yan & Stenmark, Harald Alfred (2023). Autophagosome biogenesis. Cells. 12:668(4), s. 1–15. doi: 10.3390/cells12040668. Fulltekst i vitenarkiv Vis sammendrag

  Autophagy–the lysosomal degradation of cytoplasm–plays a central role in cellular homeostasis and protects cells from potentially harmful agents that may accumulate in the cytoplasm, including pathogens, protein aggregates, and dysfunctional organelles. This process is initiated by the formation of a phagophore membrane, which wraps around a portion of cytoplasm or cargo and closes to form a double-membrane autophagosome. Upon the fusion of the autophagosome with a lysosome, the sequestered material is degraded by lysosomal hydrolases in the resulting autolysosome. Several alternative membrane sources of autophagosomes have been proposed, including the plasma membrane, endosomes, mitochondria, endoplasmic reticulum, lipid droplets, hybrid organelles, and de novo synthesis. Here, we review recent progress in our understanding of how the autophagosome is formed and highlight the proposed role of vesicles that contain the lipid scramblase ATG9 as potential seeds for phagophore biogenesis. We also discuss how the phagophore is sealed by the action of the endosomal sorting complex required for transport (ESCRT) proteins.

• Zhen, Yan & Stenmark, Harald Alfred (2023). A phosphoinositide kinase triggers migrasome formation. Cell Research. ISSN 1001-0602. 33(8), s. 577–578. doi: 10.1038/s41422-023-00822-2. Fulltekst i vitenarkiv
• Zhen, Yan; Radulovic, Maja; Vietri, Marina & Stenmark, Harald (2021). Sealing holes in cellular membranes. EMBO Journal. ISSN 0261-4189. 40:e106922, s. 1–13. doi: 10.15252/embj.2020106922. Fulltekst i vitenarkiv Vis sammendrag

  The compartmentalization of eukaryotic cells, which is essential for their viability and functions, is ensured by single or double bilayer membranes that separate the cell from the exterior and form boundaries between the cell’s organelles and the cytosol. Nascent nuclear envelopes and autophagosomes, which both are enveloped by double membranes, need to be sealed during the late stage of their biogenesis. On the other hand, the integrity of cellular membranes such as the plasma membrane, lysosomes and the nuclear envelope can be compromised by pathogens, chemicals, radiation, inflammatory responses and mechanical stress. There are cellular programmes that restore membrane integrity after injury. Here, we review cellular mechanisms that have evolved to maintain membrane integrity during organelle biogenesis and after injury, including membrane scission mediated by the endosomal sorting complex required for transport (ESCRT), vesicle patching and endocytosis.

• Zhen, Yan; Spangenberg, Helene; Munson, Michael Joseph; Brech, Andreas; Schink, Kay Oliver & Tan, Kia Wee [Vis alle 13 forfattere av denne artikkelen] (2019). ESCRT-mediated phagophore sealing during mitophagy. Autophagy. ISSN 1554-8627. s. 1–16. doi: 10.1080/15548627.2019.1639301. Fulltekst i vitenarkiv Vis sammendrag

  Inactivation of the endosomal sorting complex required for transport (ESCRT) machinery has been reported to cause autophagic defects, but the exact functions of ESCRT proteins in macroautophagy/autophagy remain incompletely understood. Using live-cell fluorescence microscopy we found that the filament-forming ESCRT-III subunit CHMP4B was recruited transiently to nascent autophagosomes during starvation-induced autophagy and mitophagy, with residence times of about 1 and 2 min, respectively. Correlative light microscopy and electron tomography revealed CHMP4B recruitment at a late step in mitophagosome formation. The autophagosomal dwell time of CHMP4B was strongly increased by depletion of the regulatory ESCRT-III subunit CHMP2A. Using a novel optogenetic closure assay we observed that depletion of CHMP2A inhibited phagophore sealing during mitophagy. Consistent with this, depletion of CHMP2A and other ESCRT-III subunits inhibited both PRKN/PARKIN-dependent and -independent mitophagy. We conclude that the ESCRT machinery mediates phagophore closure, and that this is essential for mitophagic flux.

• Kostas, Michal Janusz; Haugsten, Ellen Margrethe; Zhen, Yan; Sørensen, Vigdis; Szybowska, Patrycja Maria & Fiorito, Elisa [Vis alle 11 forfattere av denne artikkelen] (2018). Protein Tyrosine Phosphatase Receptor Type G (PTPRG) controls Fibroblast Growth Factor Receptor (FGFR) 1 activity and influences sensitivity to FGFR kinase inhibitors. Molecular & Cellular Proteomics. ISSN 1535-9476. 17(5), s. 850–870. doi: 10.1074/mcp.RA117.000538. Fulltekst i vitenarkiv Vis sammendrag

  Recently, FGFR1 was found to be overexpressed in osteosarcoma and represents an important target for precision medicine. However, because targeted cancer therapy based on FGFR inhibitors has so far been less efficient than expected, a detailed understanding of the target is important. We have here applied proximity-dependent biotin labeling combined with label-free quantitative mass spectrometry to identify determinants of FGFR1 activity in an osteosarcoma cell line. Many known FGFR interactors were identified (e.g. FRS2, PLCG1, RSK2, SRC), but the data also suggested novel determinants. A strong hit in our screen was the tyrosine phosphatase PTPRG. We show that PTPRG and FGFR1 interact and colocalize at the plasma membrane where PTPRG directly dephosphorylates activated FGFR1. We further show that osteosarcoma cell lines depleted for PTPRG display increased FGFR activity and are hypersensitive to stimulation by FGF1. In addition, PTPRG depletion elevated cell growth and negatively affected the efficacy of FGFR kinase inhibitors. Thus, PTPRG may have future clinical relevance by being a predictor of outcome after FGFR inhibitor treatment.

• Zhen, Yan; Haugsten, Ellen Margrethe; Singh, Sachin Kumar & Wesche, Jørgen (2018). Proximity Labeling by a Recombinant APEX2-FGF1 Fusion Protein Reveals Interaction of FGF1 with the Proteoglycans CD44 and CSPG4. Biochemistry. ISSN 0006-2960. 57(26), s. 3807–3816. doi: 10.1021/acs.biochem.8b00120. Fulltekst i vitenarkiv Vis sammendrag

  Fibroblast growth factor 1 (FGF1) binds to specific FGF receptors (FGFRs) at the surface of target cells to initiate intracellular signaling. While heparan sulfate proteoglycans (HSPGs) are well-described coreceptors, it is uncertain whether there are additional binding sites for FGF1 at the cell surface. To address this, we devised and tested a method to identify novel binding sites for FGF1 at the cell surface, which may also be applicable for other protein ligands. We constructed an APEX2–FGF1 fusion protein to perform proximal biotin labeling of proteins following binding of the fusion protein to the cell surface. After functional validation of the fusion protein by a signaling assay, we used this method to identify binding sites for FGF1 on cell surfaces of living cells. We confirmed the feasibility of our approach by detection of FGFR4, a well-known and specific receptor for FGF1. We subsequently screened for novel interactors using RPE1 cells and identified the proteoglycans CSPG4 (NG2) and CD44. We found that FGF1 binds CD44 through its heparin-binding moiety. Moreover, we found that FGF1 was colocalized with both CSPG4 and CD44 at the cell surface, suggesting that these receptors act as storage molecules that create a reservoir of FGF1. Importantly, our data demonstrate that recombinant ligand–APEX2 fusion proteins can be used to identify novel receptor interactions on the cell surface.

• Wendel, Torunn; Zhen, Yan; Suo, Zhenhe; Bruheim, Skjalg & Wiedlocha, Antoni (2016). The novel HSP90 inhibitor NVP-AUY922 shows synergistic anti-leukemic activity with cytarabine in vivo. Experimental Cell Research. ISSN 0014-4827. 340(2), s. 220–226. doi: 10.1016/j.yexcr.2015.12.017. Fulltekst i vitenarkiv
• Zhen, Yan & Stenmark, Harald Alfred (2015). Cellular functions of Rab GTPases at a glance. Journal of Cell Science. ISSN 0021-9533. 128(17), s. 3171–3176. doi: 10.1242/jcs.166074. Fulltekst i vitenarkiv
• Nadratowska-Wesolowska, Beata; Haugsten, Ellen Margrethe; Zakrzewska, Malgorzata; Jakimowicz, Piotr; Zhen, Yan & Pajdzik, Dorota [Vis alle 8 forfattere av denne artikkelen] (2014). RSK2 regulates endocytosis of FGF receptor 1 by phosphorylation on serine 789. Oncogene. ISSN 0950-9232. 33(40), s. 4823–4836. doi: 10.1038/onc.2013.425. Fulltekst i vitenarkiv
• Zhen, Yan; Sørensen, Vigdis; Skjerpen, Camilla Skiple; Haugsten, Ellen Margrethe; Jin, Yixin & Waelchli, Sebastien [Vis alle 8 forfattere av denne artikkelen] (2012). Nuclear Import of Exogenous FGF1 Requires the ER-Protein LRRC59 and the Importins Kpn alpha 1 and Kpn beta 1. Traffic: The moving front of cell biology. ISSN 1398-9219. 13(5), s. 650–664. doi: 10.1111/j.1600-0854.2012.01341.x. Fulltekst i vitenarkiv
• Jin, Yixin; Zhen, Yan; Haugsten, Ellen Margrethe & Wiedlocha, Antoni (2011). The driver of malignancy in KG-1a leukemic cells, FGFR1OP2-FGFR1, encodes an HSP90 addicted oncoprotein. Cellular Signalling. ISSN 0898-6568. 23(11), s. 1758–1766. doi: 10.1016/j.cellsig.2011.06.010. Fulltekst i vitenarkiv
• Shahzidi, Susan; Cunderlikova, Beata; Wiedlocha, Antoni; Zhen, Yan; Vasovic, Vlada & Nesland, Jahn M [Vis alle 7 forfattere av denne artikkelen] (2011). Simultaneously targeting mitochondria and endoplasmic reticulum by photodynamic therapy induces apoptosis in human lymphoma cells. Photochemical and Photobiological Sciences. ISSN 1474-905X. 10(11), s. 1773–1782. doi: 10.1039/c1pp05169e. Fulltekst i vitenarkiv
• Zakrzewska, Malgorzata; Zhen, Yan; Wiedlocha, Antoni; Olsnes, Sjur & Wesche, Jørgen (2009). Size Limitation in Translocation of Fibroblast Growth Factor 1 Fusion Proteins across the Endosomal Membrane. Biochemistry. ISSN 0006-2960. 48(30), s. 7209–7218. doi: 10.1021/bi9007353. Fulltekst i vitenarkiv
• Sørensen, Vigdis; Zhen, Yan; Zakrzewska, Malgorzata; Haugsten, Ellen Margrethe; Walchli, S & Nilsen, Trine [Vis alle 8 forfattere av denne artikkelen] (2008). Phosphorylation of fibroblast growth factor (FGF) receptor 1 at Ser777 by p38 mitogen-activated protein kinase regulates translocation of exogenous FGF1 to the cytosol and nucleus. Molecular and Cellular Biology. ISSN 0270-7306. 28(12), s. 4129–4141. doi: 10.1128/MCB.02117-07. Fulltekst i vitenarkiv
• Zhen, Yan; Sørensen, Vigdis; Jin, Y; Suo, Zhenhe & Wiedlocha, Antoni (2007). Indirubin-3 '-monoxime inhibits autophosphorylation of FGFR1 and stimulates ERK1/2 activity via p38 MAPK. Oncogene. ISSN 0950-9232. 26. doi: 10.1038/sj.onc.1210473. Fulltekst i vitenarkiv

Se alle arbeider i NVA

• Zhen, Yan; Olsnes, Sjur & Sandvig, Kirsten (2010). Intracellular Trafficking and Signaling of Fibroblast Growth Factor 1 and its Receptor. Universitetet i Oslo. ISSN 9788280725981. Fulltekst i vitenarkiv

Se alle arbeider i NVA