tetano
Editor, Senior Moderator
Cell Rep
. 2026 Sep 2;45(9):117742.
doi: 10.1016/j.celrep.2026.117742. Online ahead of print.
Ying Li 1 , Songjun Shao 2 , Qian Lei 3 , Chunjie Li 2 , Quanwei Yu 4 , Yuxiang Li 5 , Shui Wang 2 , Lin Li 2 , Hai Chen 2 , Ridong Huang 2 , Hui Deng 6 , Weimin Li 7 , Chengdi Wang 8
Affiliations Expand
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.
Keywords: CP: immunology; HEBP2; SARS-CoV-2; SUD2core; granule exocytosis; protein interaction.
. 2026 Sep 2;45(9):117742.
doi: 10.1016/j.celrep.2026.117742. Online ahead of print.
SARS-CoV-2 SUD2core promotes neutrophil-mediated inflammation by disabling HEBP2-mediated restraint on granule exocytosis
Ying Li 1 , Songjun Shao 2 , Qian Lei 3 , Chunjie Li 2 , Quanwei Yu 4 , Yuxiang Li 5 , Shui Wang 2 , Lin Li 2 , Hai Chen 2 , Ridong Huang 2 , Hui Deng 6 , Weimin Li 7 , Chengdi Wang 8
Affiliations Expand
- PMID: 42690932
- DOI: 10.1016/j.celrep.2026.117742
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.
Keywords: CP: immunology; HEBP2; SARS-CoV-2; SUD2core; granule exocytosis; protein interaction.