The ubiquitin-specific protease 17 is involved in virus-triggered type I IFN signaling
Authors: Bo Tan
Lu Zhang
Rui Chen
Yu Liu
Bo Zhong
Hong-Bing Shu
Journal: Cell Research (2010)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: Viral infection; signaling cascades; transcription factors; nuclear factor kappa B; interferon regulatory factor 3
Affiliations: Wuhan University, China.

Abstract:  Viral infection initiates a series of signaling cascades that activate the transcription factors nuclear factor kappa B and interferon regulatory factor 3, which collaborate to induce transcription of genes for type I interferons (IFNs) and other cytokines. Here we report that the deubiquitinating enzyme ubiquitin-specific protease 17 (USP17) is required for virus-induced RIG-I- and melanoma differentiation-associated protein-5 (MDA5)-mediated type I IFN signaling. Knockdown of endogenous USP17 inhibited virus-, cytoplasmic poly(I:C)- and poly(dA:dT)-induced activation of the IFN-beta promoter and cellular antiviral responses. We further found that knockdown of USP17 inhibited RIG-I- and MDA5-induced but not downstream activator-induced activation of the IFN-beta promoter, which was correlated with an increase in ubiquitination levels of RIG-I and MDA5. Taken together, our findings suggest that USP17 functions through deubiquitination of RIG-I and MDA5 to regulate virus-induced type I IFN signaling. 

Retracted: No

PubPeer comments:
 This trial on 200 ppl shows no effect of Lopinavir Ritonavir. There is no reason why HIV-protease (which is an aspartic protease) inhibitors would work in SARS-Cov2 - where the proteases are cysteine inhibitors. [Very very different] . , 
 In the primary ITT analysis, no benefit was observed with lopinaviru2013ritonavir treatment beyond standard care in hospitalized adult patients with severe Covid-19. There were benefits of lopinaviru2013ritonavir treatment reported on some secondary outcomes. Of note, the addition of lopinavir-ritonavir had modest benefits in clinical improvement which may be attenuated if treatment is started early and a modest numerical advantage in mortality. Duration of ICU stay was also better in the lopinavir-ritonavir group. However, the certainty of the available evidence for these observations was low. Duration of hospital and time to achieving a negative SARS-CoV-2 PCR was not different by intervention group. The certainty of the available evidence was also low. These following are highlighted when making inferences from this trial; u2022tThere was no placebo group in this trial. This was also a single center and open-label study, there was no blinding to treatment. This has potential to introduce various biases. u2022tThe viral load measurement done around randomization was at Day 1. Mean and standard deviation in Log10 copies ml were as follows: LPV-rt, 4.4 (2.0) and SoC, 3.7 (2.1) u2013 Patients in the LPV-rt group had higher viral loads at Day 1 and this difference was statistically significant (t-test: p-value=0.017 in MedCalc). This group was potential disadvantaged with regards to viral loads when the trial started. u2022tPrimary efficacy analysis was on an intention-to-treat basis and included all the patients who had undergone randomization. A modified intention-to-treat analysis that excluded three early deaths was also performed. So, 100 vs 99 for ITT and 100 vs 96 for mITT. This study seems underpowered therefore potential leading to imprecision and high uncertainty of results. The authors however do not they increased enrollment numbers to improve on this. They do not state the final minimum sample size that was required after their revised calculations. u2022tIn previous trials of SARS illnesses, LPV-rt has shown to act synergistically with ribavirin. Perhaps the authors could have considered three groups if they had sufficient numbers i.e. SoC vs. LPV-rt vs. LPV-rt with ribavirin. Its possible LPV-rt on its own may not be an adequate treatment but rather as dual or triple therapy with other antiviral agents. u2022tThis was a cohort of severely ill patients with advanced disease. They started treatment late u2013 median time from symptom onset to randomization and therefore initiation of the intervention was 13 days (11-16 days). This may have blunted benefit and meaningful differences if any. u2022tThe main outcome was time to clinical improvement (ordinal score of 7 OR hospital discharge whichever came first). While a more precise endpoint would have been desired i.e. something that can be measured with less subjectivity, it still a highly subjective endpoint (the score of 7) as it involves gauging usual functional activities that are decided by the patient. u2022tFor the main primary analysis, 3 patients in the LPV-rt arm group died before they received any LPV-rt. This analysis shows no difference between the groups in clinical improvement. In this group that was randomized approximately 2 weeks after symptom onset, when analysis was restricted to those that initiated LPV-rt earlier (within 12 days of symptom onset), patients in the LPV-rt arm had better clinical improvement and a trend towards better survival. In the mITT analysis where these 3 patients are excluded, time to clinical improvement was better in the LPV-rt group compared to SoC (HR 1.39, 95%CI 1.00-1.91). u2022tThe authors do not provide data that allows calculation of impact i.e. numbers needed to treat. This help to understand effect sizes compared to relative measures like hazard ratios. u2022tSecondary outcomes like clinical improvement at day 14, length of ICU stay and time to treatment discharge seem to favour the LPV-rt group in the main analysis. u2022tApproximately 14% of patients in the LPV-rt were prematurely discontinued from treatment due to related adverse events. This is a relatively large loss of measurements endpoints that could lead to a study being statistically underpowered. u2022tOverall judgement with regards to risk of bias is Moderate. While these findings show lack of LPV-rt benefit in the primary analysis and evidence of benefit in some secondary outcomes, this may only be applicable to hospitalised severely ill adult patients with COVID-19 thereby limiting generalizability. Furthermore, the evidence is low certainty and insufficient for one to draw conclusive inferences on the efficacy or non-efficacy of lopinavir-ritonavir for the treatment of COVID-19. There is need for well-designed prospective trials to evaluate the efficacy of lopinavir-ritonavir in COVID-19 treatment. ,