Yaowen Wu Lab

Yaowen Wu Lab concept

ImageYaowen Wu

Research Group Overview

Living systems rely on precisely regulated chemical reactions that occur with spatial and temporal specificity in response to extracellular or intracellular cues. To decipher these processes, one must both visualize and perturb the underlying chemistry. Chemical tools thus offer unparalleled capabilities to emulate or modulate biological pathways, facilitating both mechanistic investigations and the engineering of novel cellular functions (synthetic biology).

We pursue two complementary research strands:

• Biology‑driven projects, in which we tackle mechanistic questions that elude conventional biological techniques by harnessing novel chemical strategies alongside rigorous biochemical and cell‑biological analyses.
• Chemistry‑driven projects, focused on the design and synthesis of versatile chemical probes and methodologies that serve as powerful instruments for exploring diverse biological phenomena.

Together, these integrated approaches enable the discovery of previously unrecognized regulatory mechanisms and the creation of new functional modalities.

Major Research Themes

1. Autophagy and CASM

Autophagy is an evolutionarily conserved catabolic pathway in eukaryotic cells, responsible for the clearance of damaged organelles and aggregated proteins via sequestration within double‑membraned autophagosomes. Dysregulation of autophagy contributes to a spectrum of pathologies—including cancer, neurodegeneration, and infectious disease.

• Understanding autophagy by chemical genetic approaches
  We identified novel chemical scaffolds that modulate autophagy and uncovered the GRAMD1A–cholesterol axis as a key regulator of autophagosome biogenesis (Angew Chem 2017, Angew Chem 2017, Chem Sci 2018, MiMB 2018, BMC 2019, Nat Chem Biol 2019, Angew Chem 2020, Angew Chem 2020, Cell Chem Biol 2021).

• Mechanistic insights
  By integrating cell‑biological, biochemical, and structural biology methods, we have demonstrated that the small GTPase Rab33B is critical for autophagosome formation through recruitment of the E3‑like ATG16L1–ATG5–ATG12 complex to nascent autophagic membranes (Autophgay 2022) and elucidated a novel mechanism by which Legionella pneumophila subverts host autophagy (eLife 2017, Virulence 2019 review, ChemBioChem 2020).

• Noncanonical pathways (CASM)
  Our work on emerging Conjugation of ATG8 to Single Membranes (CASM) revealed small molecules (Inducin and Tantalosin) that trigger CASM and defined how the Vibrio cholerae MakA toxin induces this pathway (JCS 2021, JCB 2022, Autophagy 2022, Angew Chem 2022, ChemBioChem 2024, PNAS 2024). We and others characterized the sphingomyelin–TECPR1 axis and established TECPR1–ATG5–ATG12 as a new E3‑like ligase in lysosomal membrane repair, uncovering noncanonical functions of autophagy proteins (EMBO Rep 2023, Autophagy 2024, bioRxiv 2024).

ImageYaowen Wu

2. Membrane Trafficking and Small GTPases

Eukaryotic cells maintain compartmentalization through a sophisticated vesicular transport network. Rab GTPases act as master regulators of vesicle formation, targeting, and fusion by cycling between active and inactive states under the control of specific regulators and effectors. We investigate how these elaborate reactions are integrated at both molecular and cellular scales and how their dysregulation leads to disease. Our quantitative analyses of Rab GTPase membrane targeting have produced a comprehensive model for their localization—a framework that illuminates general principles of intracellular transport (PNAS 2014, PNAS 2016, Biochemistry 2019, MiMB 2021, MiMB 2021).

ImageYaowen Wu

3. Chemo‑optogenetics

Genetic perturbations (e.g., overexpression, knockout, knockdown) provide important insights but operate on slow timescales (hours to days), often obscuring transient phenotypes. In contrast, chemical and light‑inducible dimerization systems afford unmatched spatiotemporal precision for controlling protein activity. They have been very useful to dissect the complex biological mechanisms (JACS 2012, Curr Opin Chem Biol 2015, ChemEurJ 2019, Nat Meth 2023, reviews).

• Reversible chemically induced dimerization (CID) system
  We developed the first reversible, bioorthogonal chemically induced dimerization platform for control of protein function in living cells (Angew Chem 2014).

• First-generation chemo-optogenetic systems
  By pioneering photocaged/photocleavable molecular glues (e.g. NovcTMP‑Cl, CONC), we achieved optical control over protein functions with subcellular resolution (Angew Chem 2017, 2018). Based on these systems, we developed Molecular Activity Painting (MAP) for micrometer‑scale “painting” of signaling activities at the plasma membrane and Multi-directional Activity Control (MAC) to spatiotemporally direct cellular signaling pathways and intracellular cargo transport (Angew Chem 2018).

• Next-generation chemo-optogenetic systems
  We developed photoswitchable molecular glues (e.g. TACs, TDCs, TFCs, TCC, TPC) that act like cellular light switches, repeatedly toggling protein functions on and off with high spatial (micrometres) and temporal (seconds) precision (Angew Chem 2025, ChemEurJ 2025)

ImageYaowen Wu

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4. Protein Chemical Modification

The installation of synthetic probes—such as fluorophores, affinity tags, and specialized labels—onto proteins is essential for functional characterization in vitro and in vivo. Chemical methods have significantly broadened the toolkit for protein modification.

• Semisynthetic proteins
  Our laboratory has advanced strategies for preparing post‑translationally modified proteins, enabling studies of membrane trafficking and autophagy (ChemBioChem 2012, 2013, 2020, Topics Curr Chem 2015 review, Bioorg Med Chem 2017, MiMB 2018).

• Novel labeling methodologies
  We innovated site‑selective protein conjugation and chemoselective coupling chemistries, facilitating live‑cell imaging of dynamic processes and target identification (Angew Chem 2011, JPS 2014, JACS 2014, Chem Comm 2015, Org Bioorg Chem 2016 review, Angew Chem 2016, MiMB 2019, Chem Sci 2022).

These chemical biology innovations not only drive our own research but also contribute broadly applicable tools to the life science community.

 

ImageYaowen Wu

Biography of the PI

Yaowen Wu received his BS in Chemistry from Sun Yat-sen University in 2001 and his MS in Organic Chemistry from Tsinghua University in 2004 in China. After graduating as Dr rer. nat. (2008) at the Technische Universität Dortmund working at the Max Planck Institute of Molecular Physiology in Germany and a postdoctoral study in cell biology at King’s College London, he has been leader of an Otto Hahn group at the Max Planck Institute in Dortmund since 2010. Since 2012, he has been group leader of Chemical Genomics Centre of the Max Planck Society. He was then appointed as Professor in Biochemistry at the Umeå University in 2018. He has served as Director of Umeå Centre for Microbial Research (UCMR) since 2020.

His research group develops small molecules and new chemical methods to modify proteins or manipulate protein function in the context of biological systems with a particular focus on regulatory mechanisms in membrane trafficking and autophagy. He has received awards and honors including Göran Gustafsson Prize in Molecular Biology “for his innovative molecular studies of intracellular transport and autophagy” (awarded by Royal Swedish Academy of Sciences annually to one outstanding scientist of < 45 years old in each field of mathematics, physics, chemistry, molecular biology and medicine), "Future of Biochemistry" recognized by “tackling problem that transcend traditional field boundaries and challenges” in the field of biochemistry, Wallenberg Academy Fellow (Royal Swedish Academy of Sciences), European Research Council (ERC) Investigator, Behrens-Weise Award, Biomedicine Research Prize and Otto-Hahn Award (selected as the single awardee of the Otto-Hahn Group Leader in 2009 in the biomedical section of the Max Planck Society).

Selected recent publications:

1. Zhang J, Herzog LK, Corkery DP, Lin TC, Klewer L, Chen X, Xin X, Li Y, Wu YW*. (2025) Modular Photoswitchable Molecular Glues for Chemo-Optogenetic Control of Protein Function in Living Cells. Angew Chem Int Ed. e202416456. (featured as Hot Paper)

2. Knyazeva A, Li S, Corkery D, Shankar K, Herzog L, Zhang X, Singh B, Niggemeyer G, Grill D, Gilthorpe J, Gaetani M, Carlson LA, Waldmann H, Wu YW*. (2024) Chemogenetic inhibition of IST1-CHMP1B interaction impairs endosomal recycling and promotes unconventional LC3 lipidation at stalled endosomes. Proc. Natl. Acad. Sci. U. S. A. 121 (17), e2317680121.

3. Corkery DP, Castro-Gonzalez S, Knyazeva A, Herzog LK, Wu YW*. (2023) An ATG12-ATG5-TECPR1 E3-like complex regulates unconventional LC3 lipidation at damaged lysosomes. EMBO Rep: e56841.

   Comment in Florey O. TECPR1 helps bridge the CASM during lysosome damage. EMBO J.  2023: e115210; Comment in Deretic V, Klionsky, DJ. (2024) An expanding repertoire of E3 ligases in membrane Atg8ylation. Nat Cell Biol. 26: 307–308.

4. Laraia L, Friese A, Corkery DP, Konstantinidis G, Erwin N, Hofer W, Karatas H, Klewer L, Brockmeyer A, Metz M, Schölermann B, Dwivedi M, Li L, Rios-Munoz P, Köhn M, Winter R, Vetter IR, Ziegler S, Janning P, Wu YW*, Waldmann H*. (2019) The cholesterol transfer protein GRAMD1A regulates autophagosome biogenesis. Nat. Chem. Biol. 15(7):710-720.

   Comment in Aldrich LN. Lipids lead the way. Nat. Chem. Biol. 2019, 15(7):653-654

5. Chen X, Wu YW*. (2018) Tunable and photoswitchable chemically induced dimerization for chemo-optogenetic control of protein and organelle positioning. Angew. Chem. Int. Ed. 57 (23): 6796-6799.

6. Yang A, Pantoom S, Wu YW*. (2017) Elucidation of anti-autophagy mechanism of the Legionella effector RavZ using semisynthetic LC3 proteins. eLife. pii: e23905.

7. Chen X, Venkatachalapathy M, Kamps D, Weigel S, Kumar R, Orlich M, Garrecht R, Hirtz M, Niemeyer CM, Wu YW*, Dehmelt L*. (2017) “Molecular Activity Painting”: Switch-like, light-controlled perturbations inside living cells. Angew. Chem. Int. Ed. 56 (21):5916-5920 (Hot paper, inside cover story)

8. Voss S, Krüger DM, Koch O, Wu YW*. (2016) Spatiotemporal imaging of small GTPases activity in live cells. Proc. Natl. Acad. Sci. U. S. A. 113 (50):14348-14353.

9. Liu P, Calderon A, Konstantinidis G, Hou J, Voss S, Chen X, Li F, Banerjee S, Hoffmann JE, Theiss C, Dehmelt L, Wu YW*. (2014) A bioorthogonal small-molecule switch system for controlling protein function in live cells. Angew. Chem. Int. Ed. 53 (38):10049-55.

10. Li F, Yi L, Zhao L, Itzen A, Goody RS, Wu YW*. (2014) The role of the hypervariable C-terminal domain in Rab membrane targeting. Proc. Natl. Acad. Sci. U. S. A. 111 (7): 2572-7.  Recommended by Faculty1000

Full list of publications