Biology subjects

Zhang, C.-S.

Publications and source records attributed to Zhang, C.-S..

4 recordsLinked to original sources

bioRxiv2023

AMPK targets PDZD8 to trigger carbon source shift to glutamine

The shift of carbon utilisation from glucose to other nutrients is a fundamental metabolic adaptation to cope with the decreased glucose oxidation during fasting or starvation1. AMP-activated protein kinase (AMPK) plays crucial roles in manifesting physiological benefits accompanying glucose starvation or calorie restriction2. However, the underlying mechanisms are unclear. Here, we show that low glucose-induced activation of AMPK plays a decisive role in the shift of carbon utilisation from glucose to glutamine. We demonstrate that endoplasmic reticulum (ER)-localised PDZD8, which we identify to be a new substrate of AMPK, is required for the glucose starvation-promoted glutaminolysis. AMPK phosphorylates PDZD8 at threonine 527 (T527), and promotes it to interact with and activate the mitochondrial glutaminase 1 (GLS1), a rate-limiting enzyme of glutaminolysis3-5, and as a result the ER-mitochondria contact is strengthened. In vivo, PDZD8 enhances glutaminolysis, and triggers mitohormesis that is required for extension of lifespan and healthspan in Caenorhabditis elegans subjected to glucose starvation or caloric restriction. Muscle-specific re-introduction of wildtype PDZD8, but not the AMPK-unphosphorylable PDZD8-T527A mutant, to PDZD8-/- mice is able to rescue the increase of glutaminolysis, and the rejuvenating effects of caloric restriction in aged mice, including grip strength and running capacity. Together, these findings reveal an AMPK-PDZD8-GLS1 axis that promotes glutaminolysis and executes the anti-ageing effects of calorie restriction by promoting inter-organelle crosstalk between ER and mitochondria.

cell biology↗

bioRxiv2023

A cleaved METTL3 potentiates the METTL3-WTAP interaction and breast cancer progression

N6-methyladenosine (m6A) methylation of RNA by the methyltransferase complex (MTC), with core components including METTL3-METTL14 heterodimers and Wilms tumor 1-associated protein (WTAP), contributes to breast tumorigenesis, but the underlying regulatory mechanisms remain elusive. Here, we identify a novel cleaved form METTL3a (residues 239-580 of METTL3). We find that METTL3a is required for the METTL3-WTAP interaction, RNA m6A deposition, as well as cancer cell proliferation. Mechanistically, we find that METTL3a is essential for the METTL3-METTL3 interaction, which is a prerequisite step for recruitment of WTAP in MTC. Analysis of m6A sequencing data shows that depletion of METTL3a globally disrupts m6A deposition, and METTL3a mediates mTOR activation via m6A-mediated suppression of TMEM127 expression. Moreover, we find that METTL3 cleavage is mediated by proteasome in an mTOR-dependent manner, revealing positive regulatory feedback between METTL3a and mTOR signaling. Our findings reveal METTL3a as an important component of MTC, and suggest the METTL3a-mTOR axis as a potential therapeutic target for breast cancer.

cell biology↗

bioRxiv2022

Specific Pupylation as IDEntity Reporter (SPIDER) for the identification of Protein-Biomolecule interactions

Protein-biomolecule interactions play pivotal roles in almost all biological processes, the identification of the interacting protein is essential. By combining a substrate-based proximity labelling activity from the pupylation pathway of Mycobacterium tuberculosis, and the streptavidin (SA)-biotin system, we developed Specific Pupylation as IDEntity Reporter (SPIDER) for identifying protein-biomolecular interactions. As a proof of principle, SPIDER was successfully applied for global identification of interacting proteins, including substrates for enzyme (CobB), the readers of m6A, the protein interactome of mRNA, and the target proteins of drug (lenalidomide). In addition, by SPIDER, we identified SARS-CoV-2 Omicron variant specific receptors on cell membrane and performed in-depth analysis for one candidate, Protein-g. These potential receptors could explain the differences between the Omicron variant and the Prototype strain, and further serve as target for combating the Omicron variant. Overall, we provide a robust technology which is applicable for a wide-range of protein-biomolecular interaction studies.

systems biology↗

bioRxiv2021

Midkine noncanonically suppresses AMPK activation through disrupting the LKB1-STRAD-Mo25 complex

Midkine (MDK), an extracellular growth factor, regulates signal transduction and cancer progression by interacting with receptors, and it can be internalized into the cytoplasm by endocytosis. However, its intracellular function and signaling regulation remain unclear. Here, we show that intracellular MDK interacts with LKB1 and STRAD to disrupt the LKB1-STRAD-Mo25 complex. Consequently, MDK decreases the activity of LKB1 to dampen both the basal and stress-induced activation of AMPK by glucose starvation or treatment of 2-DG. We also found that MDK accelerates cancer cell proliferation by inhibiting the activation of the LKB1-AMPK axis. In human cancers, compared to other well-known growth factors, MDK expression is most significantly upregulated in cancers, especially in liver, kidney and breast cancers, correlating with clinical outcomes and inversely correlating with PRKAA1 (encoding AMPK1) expression and phosphorylated AMPK levels. Our study elucidates an inhibitory mechanism for AMPK activation, which is mediated by the intracellular MDK through disrupting the LKB1-STRAD-Mo25 complex.

cancer biology↗