SARS-CoV-2 proteins manipulate autophagy

The ongoing coronavirus pandemic (COVID-19) has claimed more than 4.1 million lives worldwide. This pandemic is caused by a novel single-stranded RNA virus, namely, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that was first reported in 2019 in Wuhan, China. The rapid spread of this virus is attributed to its high infectiousness and its ability to escape and counteract host immune responses, e.g., autophagy.

What is autophagy?

Autophagy is an evolutionarily ancient auto-digestive system that plays a vital role in the antiviral defenses of the host. It targets a virus or viral components for lysosomal degradation. Several viruses develop means to evade the lysosome-dependent degradation by autophagy. These viruses sometimes evolve to manipulate the autophagic machinery such that no inhibition is encountered during viral replication, membrane trafficking, and fusion processes.

Study: Manipulation of autophagy by SARS-CoV-2 proteins. Image Credit: Kateryna Kon / Shutterstock
Study: Manipulation of autophagy by SARS-CoV-2 proteins. Image Credit: Kateryna Kon / Shutterstock

SARS-CoV-2 reduces autophagic flux in humans

Previous research has revealed that infection of human cells with SARS-CoV-2 decreases autophagic flux. This can be evaluated by studying two markers, i.e., the increased presence of the processed form of LC3B and LC3B-II and an accumulation of SQSTM1. In vitro studies revealed that the virus was not greatly affected by the initiation of autophagy using rapamycin, but remained sensitive to innate immune stimulation via interferons. This experiment showed that SARS-CoV-2 could efficiently evade the antiviral functions of autophagy.

The molecular mechanism behind the evasion of antiviral functions of autophagy by SARS-CoV-2

A new study published in the journal Autophagy details a systematic analysis of the impacts of SARS-CoV-2 proteins on autophagy. In this study, researchers analyzed the impact of 29 out of the 30 known SARS-CoV-2 proteins on autophagy. They found a decrease in the number of LC3B-positive autophagosomes in the presence of Nsp15. The researchers conducted a Western Blotting analysis and found that Nsp15 affects the MTOR axis. Additionally, the expression of viral proteins such as envelope (E), membrane (M), ORF3a, and ORF7a resulted in a robust accumulation of membrane-associated LC3B.

The authors of this study re-examined the role of the proteins on autophagosome numbers to understand if the accumulation of LC3B is associated with de novo induction of autophagy or rather caused by a block of autophagic flux. The activation of autophagy by rapamycin showed no impact on E, M, ORF3a, and ORF7a. Further, bafilomycin A1 masks their effects. The results indicate that these viral proteins prevent autophagic flux. Similarly, the expression of E, ORF3a, ORF7a, and Nsp15 causes the accumulation of SQSTM1.

The researchers of this study have reported that even though M protein triggers LC3B processing and increases LC3B-membrane localization, it does not restrict SQSTM1 degradation. This result indicates that this viral protein does not inhibit classical autophagy. The study also found SARS-CoV-2 ORF3a, ORF7a, M, and Nsp15 in autophagy to be a conserved sequence. When comparing sequences, the closest similarity was found with the conserved sequences of bat coronavirus RaTG13 and SARS-CoV-1.

Role of ORF3a and ORF7 in autophagic flux

The researchers conducted a proteomic analysis to assess the molecular mechanisms by which ORF3a and ORF7a block autophagic flux. They found both ORF3a and ORF7a colocalize with late endosomal markers and trans-Golgi network markers. However, these do not localize with early endosomal markers. The pH-sensitive molecular probes were used to study the maturation of autophagosomes and with the help of the mCherry-GFP-LC3B reporter system, researchers found that both ORF3a and ORF7a prevent the acidification of autophagosomes. This study has further reported that ORF7a lowers the number of acidic lysosomes, whilst ORF3a enhances their accumulation.

This result indicates that ORF7a lowers lysosome acidity and promotes autophagosomal degradation, whereas ORF3a blocks fusion between lysosomes and autophagosomes.

Another exciting outcome of the current study is that ORF7a-mediated deacidification of lysosomes may lead to the release of virions by avoiding degradation. Additionally, the viral E protein might be responsible for redirecting autophagosomes to assist SARS-CoV-2 virion release through the lysosomal route.

Conclusions

The authors of the current study have reported the proteins that are used by SARS-CoV-2 to manipulate autophagy. They have also highlighted the molecular mechanisms of ORF3a and ORF7a in autophagic. These results help in understanding the pathogenesis of SARS-CoV-2 and the mechanisms via which they evade autophagy induction. This research has also paved the way for future studies to understand how E, M, and Nsp15 modulate autophagy.

Journal reference:
Dr. Priyom Bose

Written by

Dr. Priyom Bose

Priyom holds a Ph.D. in Plant Biology and Biotechnology from the University of Madras, India. She is an active researcher and an experienced science writer. Priyom has also co-authored several original research articles that have been published in reputed peer-reviewed journals. She is also an avid reader and an amateur photographer.

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