Structural basis of nidovirus replication organelle evolution revealed by the arterivirus DMV pore complex
Dr. Tingting Yang (Post-doctoral Fellow)
[Supervisor: Professor Tao Ni]

Corona- and arteriviruses are distantly related positive-stranded RNA virus families within the order Nidovirales. Both remodel host membranes into double-membrane vesicles (DMVs) to shield viral RNA synthesis from immune sensors. While coronaviruses export newly synthesized RNA through a massive DMV pore complex formed by viral non-structural proteins (nsps), it remained unknown whether this architecture is unique to large-genome coronaviruses or a universal hallmark of the order. By integrating in situ cryo-electron tomography and single-particle cryo-electron microscopy, we resolved the atomic structure of the DMV pore complex from Equine Arteritis Virus (EAV), a prototype arterivirus with a small genome. Despite lacking obvious sequence homology, the minimal EAV pore shares conserved architectural principles with its elaborate coronavirus counterpart. Functionally, the complex preserves a positively charged central channel essential for viral replication and transport. These findings provide new insights into the evolutionary relationships within Nidovirales: despite differences in genome size and virion morphology, nidovirus replication organelles display remarkable evolutionary conservation at the atomic structural level, unifying the order through this conserved DMV pore complex.

Identifying genetic vulnerabilities in patient-derived gastric cancer organoids by CRISPR-Cas9 screening
Dr. Chu Zhang (Post-doctoral Fellow)
[Supervisor: Professor Alan Wong]

Identifying vulnerabilities across diverse tumour subtypes for precision therapy remains challenging. While CRISPR screens help uncover cancer targets, traditional two-dimensional (2D) cultures fail to mimic their vivo tumour environment. Here, we establish a CRISPR dropout screening pipeline using patients-derived gastric cancer organoids. Our organoid-based sub-pool screens reveal both shared and subtype-specific vulnerabilities. Expanding to genome-wide screens, we identify key targets that are not detected in 2D or 3D spheroid cultures. Genetic and pharmacological inhibition of these targets impair organoid growth and tumour formation in vivo. Our findings demonstrate the advantages of organoid-based CRISPR screening for discovering clinically actionable targets, advancing precision oncology strategies.

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