Ying Li, Songjun Shao, Qian Lei, Chunjie Li, Quanwei Yu, Yuxiang Li, Shui Wang, Lin Li, Hai Chen, Ridong Huang, Hui Deng, Weimin Li, Chengdi Wang
The molecular basis of neutrophil-driven immunopathology in severe coronavirus disease 2019 (COVID-19) remains poorly defined. Here, we identify the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) SARS-unique domain (SUD)2core domain as a direct binding partner of the neutrophil-associated protein heme binding protein 2 (HEBP2). We show that HEBP2 normally suppresses azurophilic granule exocytosis, whereas SUD2core recruits the E3 ligase LTN1 to ubiquitinate and degrade HEBP2, thereby activating the Rab27a-Synaptotagmin Like 1 (SYTL1) axis to promote granule release, NETosis, and pro-inflammatory cytokine secretion. In a human immuno-epithelial organoid co-culture model, SUD2core amplifies epithelial damage in an HEBP2-dependent manner. Importantly, two small-molecule compounds that disrupt the SUD2core-HEBP2 interaction effectively attenuate neutrophil-mediated inflammation. These findings reveal a viral strategy that dismantles host restraint on neutrophil effector functions and highlight the SUD2core-HEBP2 interface as a promising therapeutic target for COVID-19.