Related Experiment Video
Updated: Sep 5, 2026
Monitoring Neutrophil Elastase and Cathepsin G Activity in Human Sputum Samples
Published on: May 21, 2021
SARS-CoV-2 SUD2core promotes neutrophil-mediated inflammation by disabling HEBP2-mediated restraint on granule
Ying Li1, Songjun Shao2, Qian Lei1
1Department of Pulmonary and Critical Care Medicine, State Key Laboratory of Respiratory Health and Multimorbidity, West China Hospital, Sichuan University, Chengdu, China; Institute of Respiratory Health, Targeted Tracer Research and Development Laboratory, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China; Precision Medicine Center, Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, China.
Abstract:
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.
