SUMOylation restrains ACE2 degradation through TOLLIP-mediated selective autophagy to facilitate the host susceptibility to SARS-CoV-2 infection (preprint)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the ongoing coronavirus disease 2019 (COVID-19) pandemic. Alongside investigations into the virology of SARS-CoV-2, understanding the host–virus dependencies are vital for the identification and rational design of effective antiviral therapy. Here, we report the dominant SARS-CoV-2 entry receptor, ACE2, conjugates with small ubiquitin-like modifier 3 (SUMO3) through a proteome-wide protein interaction analysis. We further demonstrate that E3 SUMO ligase PIAS4 prompts the SUMOylation and stabilization of ACE2, whereas deSUMOylation enzyme SENP3 reverses this process. Conjugation of SUMO3 with ACE2 at lysine (K) 187 hampers the K48-linked ubiquitination of ACE2, thus suppressing its subsequent cargo receptor TOLLIP-dependent autophagic degradation. Pharmacological intervention of ACE2 SUMOylation blocks the entry of SARS-CoV-2 and viral infection-triggered immune responses. Collectively, our findings suggest selective autophagic degradation of ACE2 orchestrated by SUMOylation and ubiquitination can be targeted to future antiviral therapy of SARS-CoV-2.

The interval between onset and admission predicts disease progression in COVID-19 patients.

BACKGROUND: The prognostic role of the interval between disease onset and hospital admission (O-A interval) was undetermined in patients with the coronavirus disease 2019 (COVID-19). METHODS: A total of 205 laboratory-confirmed inpatients admitted to Hankou hospital of Wuhan from January 11 to March 8, 2020 were consecutively included in this retrospective observational study. Demographic data, medical history, laboratory testing results were collected from medical records. Univariate and multivariate logistic regression models were used to evaluate the prognostic effect of the O-A interval (≤7 versus >7 days) on disease progression in mild-to-moderate patients. For severe-to-critical patients, the in-hospital mortality and the length of hospital stay were compared between the O-A interval subgroups using log-rank test and Mann-Whitney U test, respectively. RESULTS: Mild-to-moderate patients with a short O-A interval (≤7 days) are more likely to deteriorate to severe-to-critical stage compared to those with a long O-A interval (>7 days) [unadjusted odds ratio =2.93, 95% confidence interval (CI), 1.32-6.55; adjusted odds ratio =3.44, 95% CI, 1.20-9.83]. No association was identified between the O-A interval and the mortality or the length of hospital stay of severe-to-critical patients. CONCLUSIONS: The O-A interval has predictive values for the disease progression in mild-to-moderate COVID-19 patients. Under circumstances of the specific health system in Wuhan, China, the spontaneous healthcare-seeking behavior is usually determined by patients' own heath conditions. Hence, the O-A interval can be reflective of the natural course of COVID-19 to some extent. However, our findings should be validated further in other cohorts and in other health systems.