Autophagy
Autophagy is a highly conserved catabolic process in which specialized degradative vesicles, autophagosomes, are formed. It has been reported to be involved in many cellular processes and human diseases, such as cancer and neurodegeneration. Using Drosophila and mammalian cells as model systems, my study identified a novel autophagy regulator, myosin II, linking two main regulators - Atg1 and Atg9. The autophagy- essential kinase Atg1 can activate myosin-II to drive transport of Atg9, which provides a source of membrane for autophagosomes (HW Tang. et al, The EMBO Journal, 2011; HW Tang. et al, Autophagy, 2011). This work was also selected by Nature Reviews Molecular Cell Biology, A- IMBN Research, and EMBO J. as a Research Highlight. In addition, I also worked with different collaborators to place new players into the autophagy regulatory network, such as Hsp27, paxillin, Trabid, Dwg, and UBE3C (GC Chen. et al, Autophagy, 2008; SF Chen, et al, Journal of biomedical science, 2012; YH Chen, et al., Nature communications, 2021; Y Wang. et al, Cells, 2022; HW Tang. et al, Nature communications, 2023).
Using Drosophila as a discovery engine, our research found a novel role of Atg9 in regulating ROS-induced JNK activation and JNK-dependent stress responses including autophagy induction, cell death, and stem cell proliferation. ROS-induced autophagy can feedback negative inhibit JNK activation by modulation of Atg9 (HW Tang. et al, Developmental cell, 2013).
mTOR
To identify the new players of mTORC1 signaling, I used genetic, biochemical, and quantitative mass spectrometry approaches to identify the cleavage and polyadenylation (CPA) complex and m6A methyltransferase complex (MTC) as downstream effectors of mTORC1 signaling. The CPA complex is required for cleavage and polyadenylation of pre-mRNAs, and its depletion can induce alternative mRNA splicing and polyadenylation of specific transcripts. While most studies focus on TORC1 regulation and downstream processes in the cytoplasm, my mechanistic studies showed that mTORC1 signaling induces phosphorylation of CPSF6, a key component of the CPA complex. Phosphorylated CPSF6 translocates to the nucleus and induces alternative RNA processing of transcripts involved in autophagy, lipid storage, protein synthesis, and energy metabolism. My study further found that mTORC1 stabilizes MTC via activation of the chaperonin CCT complex and upregulate m6A modification to promote the degradation of ATG transcripts, unveiling an mTORC1-signaling cascade that regulates m6A RNA methylation and autophagy (HW Tang. et al., PNAS, 2021). I also collaborated with other lab to characterize new components of MTC and identify novel targets of mTORC1 signaling.
PROJECTS
Investigate the regulatory mechanisms underlying tumorigenesis and how advanced tumors induce muscle wasting