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Background: Since the introduction of BNT162b2 mRNA COVID-19 vaccine by Pfizer in late 2020, efficacy and immunogenicity waning of COVID-19 vaccines was reported, and decision making regarding a booster remains a top priority worldwide, a decision that should be made based on breakthrough infection rate and antibody titer decline overtime., Methods: We conducted a 5-month longitudinal prospective study involving vaccinated healthcare personnel, who were tested monthly for antibody titer, and sampled biweekly and on clinical indication for SARS-COV-2 polymerase chain reaction (PCR), to determine antibody decline and breakthrough infection., Results: 100 participants were recruited to the study. Antibody titer reached the climate after one month of the second dose of the vaccine, and declined rapidly thereafter: the median antibody levels were 895; 22,266; 9,682; 2,554 and 1,401 AU/ml in the day of the second dose, and in one month interval thereafter, respectively. In other words, four months after vaccination, the mean antibody level was 6% of the peak levels. During the study period, 4 breakthrough infections were diagnosed, 2 of which were asymptomatic, and the remaining two were mild cases; sharp elevation of antibody titer was seen after infection., Conclusion: Antibody titer drops rapidly one month after the second dose of the vaccine. All infections within the study period were mild or asymptomatic, after which titer elevations were seen., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

A hallmark of cancer is dysregulated protein turnover (proteostasis), which involves pathologic ubiquitin-dependent degradation of tumor suppressor proteins, as well as increased oncoprotein stabilization. The latter is due, in part, to mutation within sequences, termed degrons, which are required for oncoprotein recognition by the substrate-recognition enzyme, E3 ubiquitin ligase. Stabilization may also result from the inactivation of the enzymatic machinery that mediates the degradation of oncoproteins. Importantly, inactivation in cancer of E3 enzymes that regulates the physiological degradation of oncoproteins, results in tumor cells that accumulate multiple active oncoproteins with prolonged half-lives, leading to the development of "degradation-resistant" cancer cells. In addition, specific sequences may enable ubiquitinated proteins to evade degradation at the 26S proteasome. While the ubiquitin-proteasome pathway was originally discovered as central for protein degradation, in cancer cells a ubiquitin-dependent protein stabilization pathway actively translates transient mitogenic signals into long-lasting protein stabilization and enhances the activity of key oncoproteins. A central enzyme in this pathway is the ubiquitin ligase RNF4. An intimate link connects protein stabilization with tumorigenesis in experimental models as well as in the clinic, suggesting that pharmacological inhibition of protein stabilization has potential for personalized medicine in cancer. In this review, we highlight old observations and recent advances in our knowledge regarding protein stabilization.

Among the hallmarks of melanoma are impaired proteostasis and rapid development of resistance to targeted therapy that represent a major clinical challenge. However, the molecular machinery that links these processes is unknown. Here we describe that by stabilizing key melanoma oncoproteins, the ubiquitin ligase RNF4 promotes tumorigenesis and confers resistance to targeted therapy in melanoma cells, xenograft mouse models, and patient samples. In patients, RNF4 protein and mRNA levels correlate with poor prognosis and with resistance to MAPK inhibitors. Remarkably, RNF4 tumorigenic properties, including therapy resistance, require the translation initiation factor initiation elongation factor alpha (eIF2α). RNF4 binds, ubiquitinates, and stabilizes the phosphorylated eIF2α (p-eIF2α) but not activating transcription factor 4 or C/EBP homologous protein that mediates the eIF2α-dependent integrated stress response. In accordance, p-eIF2α levels were significantly elevated in high-RNF4 patient-derived melanomas. Thus, RNF4 and p-eIF2α establish a positive feed-forward loop connecting oncogenic translation and ubiquitin-dependent protein stabilization in melanoma., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)