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Biology subjects

Bretones, G.

Publications and source records attributed to Bretones, G..

3 recordsLinked to original sources
bioRxiv2023

Host factor PLAC8 is required for pancreas infection by SARS-CoV-2

BackgroundAlthough COVID-19 initially caused great concern about respiratory symptoms, mounting evidence shows that also the pancreas is productively infected by SARS-CoV-2. However, the severity of pancreatic SARS-CoV-2 infection and its pathophysiology are still under debate. Here we investigated the consequences of SARS-CoV-2 pancreatic infection and the role of the host factor Placenta-associated protein (PLAC8) MethodsWe analyzed plasma levels of pancreatic enzymes and inflammatory markers in a retrospective cohort study of 120 COVID-19 patients distributed in 3 severity-stratified groups. We studied the expression of SARS-CoV-2 and PLAC8 in the pancreas of deceased COVID-19 patients as well as in non-infected donors. We performed infection experiments in PLAC8 knock-out PDAC cell lines with full SARS-CoV-2 virus. ResultsWe found that analysis of circulating pancreatic enzymes aided the stratification of patients according to COVID-19 severity and predict outcomes. Interestingly, we found an association between PLAC8 expression and SARS-CoV-2 infection in postmortem analysis of COVID-19 patients. Using full SARS-CoV-2 infectious virus inoculum from Wuhan-1 and BA.1 strains, we demonstrated that PLAC8 is necessary for productive infection of PDAC cell lines. Finally, we observed an overlap between PLAC8 and SARS-CoV-2 immunoreactivities of the pancreas of deceased patients. ConclusionOur data indicate the human pancreas as a SARS-CoV-2 target with plausible signs of injury and demonstrate that the host factor PLAC8 is required for SARS-CoV-2 pancreatic infection, thus defining new target opportunities for COVID-19-associated pancreatic pathogenesis. Plain language summaryPrevious studies have shown that the pancreas is infected by SARS-CoV-2. However, none of these studies have described measurable pancreatic damage associated to COVID-19 severity and the pathogenesis of pancreatic SARS-CoV-2 infection remains largely unknown. Novel host factors have been proposed for SARS-CoV-2 infection of mainly the airway epithelium, none of them studied in the pancreas. Our study shows clinically relevant pancreatic damage associated with SARS-CoV-2 infiltration and assesses the predictive potential of circulating pancreatic enzymes to stratify patients according to COVID-19 severity and predict clinical outcomes in a cohort of 120 patients. Our data show that host factor Placenta-associated protein 8 (PLAC8) expression is linked to SARS-CoV-2 infection in postmortem analysis of COVID-19 patients and functionally demonstrated the full requirement of PLAC8 for SARS-CoV-2 pancreatic infection and viral replication. Our data confirm the human pancreas as a SARS-CoV-2 target with signs of injury unveiling the measurement of pancreatic enzymes for prognosis value and demonstrating that host factor PLAC8 is required for SARS-CoV-2 pancreatic infection defining new stratification and target opportunities for COVID-19-associated pancreatic pathogenesis.

cell biology↗
bioRxiv2018

Myc stimulates cell cycle progression through the activation of Cdk1 and phosphorylation of p27

Cell cycle stimulation is a major transforming mechanism of Myc oncoprotein. This is achieved through at least three concomitant mechanisms: upregulation of cyclins and Cdks, downregulation of Cdk inhibitors p15 and p21 and the degradation of p27. The Myc-p27 antagonism has been shown to be relevant in human cancer. To be degraded, p27 must be phosphorylated at Thr-187 to be recognized by Skp2, a component of the ubiquitination complex. We previously described that Myc induces Skp2 expression. Here we show that not only Cdk2 but Cdk1 phosphorylates p27 at the Thr187, which was previously unreported. Moreover, Myc induced p27 degradation in murine fibroblasts through Cdk1 activation, which was achieved by Myc-dependent cyclin A and B induction. In the absence of Cdk2, p27 phosphorylation at Thr-187 was mainly carried out by cyclin A2-Cdk1 and cyclin B1-Cdk1. We also show that Cdk1 inhibition was sufficient for the synthetic lethal interaction with Myc. This result is relevant because Cdk1 is the only Cdk strictly required for cell cycle and the reported synthetic lethal interaction between Cdk1 and Myc.\n\nSummary blurbMyc antagonizes p27 activity in cancer. Myc activates Cdk1 to phosphorylate p27, marking p27 for degradation. This depends on Myc-mediated cyclin A and B induction. Cdk1 inhibition is sufficient for a synthetic lethal interaction with Myc

cancer biology↗
bioRxiv2017

The MYC antagonist MNT autoregulates its expression and supports proliferation in MAX deficient cells

MNT is a transcription factor of the MXD family. MNT-MAX dimers down-regulate genes by binding to E-box sequences, which can also be bound by MYC-MAX to activate transcription. MNT has been described as a modulator of MYC activity but little is known about MNT regulation and whether MNT has MAX-independent functions. Using a MAX deficient cell line and siRNA-mediated silencing of MAX, we show that in the absence of MAX, the total MNT levels are elevated and that MNT localizes both in the cytoplasm and the nucleus. In contrast, MNT is predominantly nuclear when MAX is expressed. MNT is required for optimal cell proliferation even in the absence of MAX, being the first report of a MAX-independent function of MNT. Interestingly, MNT forms homodimers and autoregulates its expression by repressing its own promoter. The tight MNT regulation and its activity in absence of MAX suggest its importance on cell homeostasis.

cancer biology↗