tetano
Editor, Senior Moderator
Antiviral Res
. 2025 Aug 18:106261.
doi: 10.1016/j.antiviral.2025.106261. Online ahead of print. SMAD5 phosphorylation by ALK1 is modulated by the interaction of the spike protein of SARS-CoV-2 and angiotensin-converting enzyme 2
Yoichi Teratake[SUP] 1 [/SUP], Tadashi Okamura[SUP] 2 [/SUP], Yukihito Ishizaka[SUP] 3 [/SUP]
Affiliations
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused more than 7 million worldwide deaths, but the mechanisms underlying its severe clinical outcomes remain elusive. Although attachment of the spike (S) protein of SARS-CoV-2 to angiotensin-converting enzyme 2 (ACE2), a pivotal step for infection, induces inflammation, the intracellular signals triggered by this interaction are unclear. Here, we found that S protein induced phosphorylation of SMAD family member 5 which was mediated by the bone morphologenetic protein (BMP) receptor activin receptor-like kinase 1 (ALK1) and BMP receptor type II. SMAD5 activation depended on the interaction of the cytoplasmic domains of ACE2 and ALK1. Notably, repetitive treatment with S protein increased the expression of immune-response genes, including interferon regulatory factor 1, interleukin-17A, and cysteine-cysteine chemokine motif ligand 20 (CCL20), all of which were blocked by an ALK inhibitor. In contrast, the S protein of human coronavirus NL63, a pathogen of acute respiratory infection with less severity than SARS-CoV-2 that also binds to ACE2, did not activate SMAD5. Because CCL20 recruits multiple immune cells positive for CC receptor 6, a specific receptor for CCL20, and was detected in broncho-alveolar lavage fluids of patients with respiratory failures by SARS-Cov-2, data suggest that SMAD5 activation by S protein augments the early immune response, leading to the severe clinical outcomes of SARS-CoV-2. (221).
Keywords: ACE2; ALK1; SARS-CoV-2; SMAD5 phosphorylation; spike protein.
. 2025 Aug 18:106261.
doi: 10.1016/j.antiviral.2025.106261. Online ahead of print. SMAD5 phosphorylation by ALK1 is modulated by the interaction of the spike protein of SARS-CoV-2 and angiotensin-converting enzyme 2
Yoichi Teratake[SUP] 1 [/SUP], Tadashi Okamura[SUP] 2 [/SUP], Yukihito Ishizaka[SUP] 3 [/SUP]
Affiliations
- PMID: 40835031
- DOI: 10.1016/j.antiviral.2025.106261
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused more than 7 million worldwide deaths, but the mechanisms underlying its severe clinical outcomes remain elusive. Although attachment of the spike (S) protein of SARS-CoV-2 to angiotensin-converting enzyme 2 (ACE2), a pivotal step for infection, induces inflammation, the intracellular signals triggered by this interaction are unclear. Here, we found that S protein induced phosphorylation of SMAD family member 5 which was mediated by the bone morphologenetic protein (BMP) receptor activin receptor-like kinase 1 (ALK1) and BMP receptor type II. SMAD5 activation depended on the interaction of the cytoplasmic domains of ACE2 and ALK1. Notably, repetitive treatment with S protein increased the expression of immune-response genes, including interferon regulatory factor 1, interleukin-17A, and cysteine-cysteine chemokine motif ligand 20 (CCL20), all of which were blocked by an ALK inhibitor. In contrast, the S protein of human coronavirus NL63, a pathogen of acute respiratory infection with less severity than SARS-CoV-2 that also binds to ACE2, did not activate SMAD5. Because CCL20 recruits multiple immune cells positive for CC receptor 6, a specific receptor for CCL20, and was detected in broncho-alveolar lavage fluids of patients with respiratory failures by SARS-Cov-2, data suggest that SMAD5 activation by S protein augments the early immune response, leading to the severe clinical outcomes of SARS-CoV-2. (221).
Keywords: ACE2; ALK1; SARS-CoV-2; SMAD5 phosphorylation; spike protein.