Université de Fribourg

Retromer and TBC1D5 maintain late endosomal RAB7 domains to enable amino acid–induced mTORC1 signaling

Kvainickas, Arunas ; Nägele, Heike ; Qi, Wenjing ; Dokládal, Ladislav ; Jimenez-Orgaz, Ana ; Stehl, Luca ; Gangurde, Dipak ; Zhao, Qian ; Hu, Zehan ; Dengjel, Jörn ; Virgilio, Claudio De ; Baumeister, Ralf ; Steinberg, Florian

In: The Journal of Cell Biology, 2019, vol. 218, no. 9, p. 3019–3038

Retromer is an evolutionarily conserved multiprotein complex that orchestrates the endocytic recycling of integral membrane proteins. Here, we demonstrate that retromer is also required to maintain lysosomal amino acid signaling through mTORC1 across species. Without retromer, amino acids no longer stimulate mTORC1 translocation to the lysosomal membrane, which leads to a loss of mTORC1...

Université de Fribourg

The transcription factor Spt4-Spt5 complex regulates the expression of ATG8 and ATG41

Wen, Xin ; Gatica, Damián ; Yin, Zhangyuan ; Hu, Zehan ; Dengjel, Jörn ; Klionsky, Daniel J.

In: Autophagy, 2019, vol. 0, no. 0, p. 1–14

Macroautophagy/autophagy, a highly conserved dynamic process, is one of the major degradative pathways in cells. So far, over 40 autophagy-related (ATG) genes have been identified in Saccharomyces cerevisiae, most of which have homologs in more complex eukaryotes. Autophagy plays a crucial role in cell survival and maintenance, and its dysfunction is related to various diseases, indicating...

Université de Fribourg

Multilayered control of protein turnover by torc1 and atg1

Hu, Zehan ; Raucci, Serena ; Jaquenoud, Malika ; Hatakeyama, Riko ; Stumpe, Michael ; Rohr, Rudolf ; Reggiori, Fulvio ; Virgilio, Claudio De ; Dengjel, Jörn

In: Cell Reports, 2019, vol. 28, no. 13, p. 3486-3496.e6

The target of rapamycin complex 1 (TORC1) is a master regulator of cell homeostasis, which promotes anabolic reactions and synchronously inhibits catabolic processes such as autophagy-mediated protein degradation. Its prime autophagy target is Atg13, a subunit of the Atg1 kinase complex that acts as the gatekeeper of canonical autophagy. To study whether the activities of TORC1 and Atg1 are...

Université de Fribourg

The flavonoid 4,4′-dimethoxychalcone promotes autophagy-dependent longevity across species

Carmona-Gutierrez, Didac ; Zimmermann, Andreas ; Kainz, Katharina ; Pietrocola, Federico ; Chen, Guo ; Maglioni, Silvia ; Schiavi, Alfonso ; Nah, Jihoon ; Mertel, Sara ; Beuschel, Christine B. ; Castoldi, Francesca ; Sica, Valentina ; Trausinger, Gert ; Raml, Reingard ; Sommer, Cornelia ; Schroeder, Sabrina ; Hofer, Sebastian J. ; Bauer, Maria A. ; Pendl, Tobias ; Tadic, Jelena ; Dammbrueck, Christopher ; Hu, Zehan ; Ruckenstuhl, Christoph ; Eisenberg, Tobias ; Durand, Sylvere ; Bossut, Noélie ; Aprahamian, Fanny ; Abdellatif, Mahmoud ; Sedej, Simon ; Enot, David P. ; Wolinski, Heimo ; Dengjel, Jörn ; Kepp, Oliver ; Magnes, Christoph ; Sinner, Frank ; Pieber, Thomas R. ; Sadoshima, Junichi ; Ventura, Natascia ; Sigrist, Stephan J. ; Kroemer, Guido ; Madeo, Frank

In: Nature Communications, 2019, vol. 10, no. 1, p. 651

Ageing constitutes the most important risk factor for all major chronic ailments, including malignant, cardiovascular and neurodegenerative diseases. However, behavioural and pharmacological interventions with feasible potential to promote health upon ageing remain rare. Here we report the identification of the flavonoid 4,4′- dimethoxychalcone (DMC) as a natural compound with anti-ageing...

Université de Fribourg

Spatially distinct pools of TORC1 balance protein homeostasis

Hatakeyama, Riko ; Péli-Gulli, Marie-Pierre ; Hu, Zehan ; Jaquenoud, Malika ; Osuna, Guillermo Miguel Garcia ; Sardu, Alessandro ; Dengjel, Jörn ; Virgilio, Claudio De

In: Molecular Cell, 2019, vol. 73, no. 2, p. 325-338.e8

The eukaryotic TORC1 kinase is a homeostatic controller of growth that integrates nutritional cues and mediates signals primarily from the surface of lysosomes or vacuoles. Amino acids activate TORC1 via the Rag GTPases that combine into structurally conserved multi-protein complexes such as the EGO complex (EGOC) in yeast. Here we show that Ego1, which mediates membrane-anchoring of EGOC via...

Université de Fribourg

Influenza A virus induces autophagosomal targeting of ribosomal proteins

Becker, Andrea C. ; Gannagé, Monique ; Giese, Sebastian ; Hu, Zehan ; Abou-Eid, Shadi ; Roubaty, Carole ; Paul, Petra ; Bühler, Lea ; Gretzmeier, Christine ; Dumit, Veronica I. ; Kaeser-Pebernard, Stéphanie ; Schwemmle, Martin ; Münz, Christian ; Dengjel, Jörn

In: Molecular & Cellular Proteomics, 2018, vol. 17, no. 10, p. 1909–1921

Seasonal epidemics of influenza A virus are a major cause of severe illness and are of high socio-economic relevance. For the design of effective antiviral therapies, a detailed knowledge of pathways perturbed by virus infection is critical. We performed comprehensive expression and organellar proteomics experiments to study the cellular consequences of influenza A virus infection using three...

Université de Fribourg

HUWE1 E3 ligase promotes PINK1/PARKIN-independent mitophagy by regulating AMBRA1 activation via IKKα

Rita, Anthea Di ; Peschiaroli, Angelo ; D?Acunzo, Pasquale ; Strobbe, Daniela ; Hu, Zehan ; Gruber, Jens ; Nygaard, Mads ; Lambrughi, Matteo ; Melino, Gerry ; Papaleo, Elena ; Dengjel, Jörn ; Alaoui, Said El ; Campanella, Michelangelo ; Dötsch, Volker ; Rogov, Vladimir V. ; Strappazzon, Flavie ; Cecconi, Francesco

In: Nature Communications, 2018, vol. 9, no. 1, p. 3755

The selective removal of undesired or damaged mitochondria by autophagy, known as mitophagy, is crucial for cellular homoeostasis, and prevents tumour diffusion, neurodegeneration and ageing. The pro-autophagic molecule AMBRA1 (autophagy/beclin-1 regulator-1) has been defined as a novel regulator of mitophagy in both PINK1/PARKIN-dependent and -independent systems. Here, we identified the E3...

Université de Fribourg

Role of influenza A virus NP acetylation on viral growth and replication

Giese, Sebastian ; Ciminski, Kevin ; Bolte, Hardin ; Moreira, Étori Aguiar ; Lakdawala, Seema ; Hu, Zehan ; David, Quinnlan ; Kolesnikova, Larissa ; Götz, Veronika ; Zhao, Yongxu ; Dengjel, Jörn ; Chin, Y. Eugene ; Xu, Ke ; Schwemmle, Martin

In: Nature Communications, 2017, vol. 8, no. 1, p. 1259

Lysine acetylation is a post-translational modification known to regulate protein functions. Here we identify several acetylation sites of the influenza A virus nucleoprotein (NP), including the lysine residues K77, K113 and K229. Viral growth of mutant virus encoding K229R, mimicking a non-acetylated NP lysine residue, is severely impaired compared to wildtype or the mutant viruses encoding...

Université de Fribourg

Protein glutaminylation is a yeast-specific posttranslational modification of elongation factor 1A

Jank, Thomas ; Belyi, Yury ; Wirth, Christophe ; Rospert, Sabine ; Hu, Zehan ; Dengjel, Jörn ; Tzivelekidis, Tina ; Andersen, Gregers Rom ; Hunte, Carola ; Schlosser, Andreas ; Aktories, Klaus

In: Journal of Biological Chemistry, 2017, vol. 292, no. 39, p. 16014–16023

Ribosomal translation factors are fundamental for protein synthesis and highly conserved in all kingdoms of life. The essential eukaryotic elongation factor 1A (eEF1A) delivers aminoacyl tRNAs to the A-site of the translating 80S ribosome. Several studies have revealed that eEF1A is posttranslationally modified. Using MS analysis, site-directed mutagenesis, and X-ray structural data analysis of...

Université de Fribourg

Feedback inhibition of the Rag GTPase GAP complex Lst4-Lst7 safeguards TORC1 from hyperactivation by amino acid signals

Péli-Gulli, Marie-Pierre ; Raucci, Serena ; Hu, Zehan ; Dengjel, Jörn ; Virgilio, Claudio De

In: Cell Reports, 2017, vol. 20, no. 2, p. 281–288

Amino acids stimulate the eukaryotic target of rapamycin complex 1 (TORC1), and hence growth, through the Rag GTPases and their regulators. Among these, the yeast Lst4-Lst7 Rag GTPase GAP complex clusters, as we previously reported, at the vacuolar membrane upon amino acid starvation. In response to amino acid refeeding, it activates the Rag GTPase-TORC1 branch and is then dispersed from the...