The circadian clock components BMAL1 and REV-ERBα regulate flavivirus replication

Zhuang, Xiaodong; Magrì, Andrea; Hill, Michelle L.; Lai, Alvina G.; Kumar, Abhinav; Rambhatla, Srinivasa Bhargav; Donald, Claire L.; Lopez-Clavijo, Andrea F.; Rudge, Simon A.; Pinnick, Katherine E.; Chang, Wai Hoong; Wing, Peter A C; Brown, Roger; Qin, Ximing; Simmonds, Peter; Baumert, Thomas F.; Ray, David; Loudon, A. S. I.; Balfe, Peter; Wakelam, Michael J.O.; Butterworth, Sam; Kohl, Alain; Jopling, Catherine L.; Zitzmann, Nicole; McKeating, Jane A.

doi:10.1038/s41467-019-08299-7

Cited by 80 publications

(68 citation statements)

References 66 publications

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“…This is of high significance as it not only identifies REV-ERB as an important cold-induced gene but it also demonstrates that massive upregulation of REV-ERB is sufficient to control phase resetting in mammalian cells. Finally, given that REV-ERB is a key chromatin regulator linking circadian rhythms with metabolism (Cho et al, 2012;Zhang et al, 2015), inflammation (Pariollaud et al, 2018) and cardiac surgery outcomes (Montaigne et al, 2018), and has tumor suppressor (Sulli et al, 2018) and anti-viral properties (Zhuang et al, 2019), the recognition that REV-ERB expression can be boosted more than ten-fold by 18°C exposure will be of significance for the development of novel strategies that broaden the applications of controlled deep hypothermia.…”

Section: Discussionmentioning

confidence: 99%

Cold induced chromatin compaction and nuclear retention of clock mRNAs resets the circadian rhythm

Fischl

McManus

Oldenkamp

et al. 2020

Preprint

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Cooling patients to sub-physiological temperatures is an integral part of modern medicine. We show that cold exposure induces temperature-specific changes to the higher-order chromatin and gene expression profiles of human cells. These changes are particularly dramatic at 18°C, a temperature synonymous with that experienced by patients undergoing controlled deephypothermia during surgery. Cells exposed to 18°C exhibit largely nuclear-restricted transcriptome changes. These include the nuclear accumulation of core circadian clock suppressor gene transcripts, most notably REV-ERBα. This response is accompanied by compaction of higher-order chromatin and hindrance of mRNPs from engaging nuclear pores.Rewarming reverses chromatin compaction and releases the transcripts into the cytoplasm, triggering a pulse of suppressor gene proteins that resets the circadian clock. We show that cold-induced upregulation of REV-ERBα alone is sufficient to trigger this resetting. Our findings uncover principles of the cellular cold-response that must be considered for current and future applications involving therapeutic deep-hypothermia.

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Section: Discussionmentioning

confidence: 99%

Cold induced chromatin compaction and nuclear retention of clock mRNAs resets the circadian rhythm

Fischl

McManus

Oldenkamp

et al. 2020

Preprint

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“…The dry extract was re-suspended in chloroform/MeOH (1:1). Phosphatidylethanolamine (PE) and phosphatidylserine (PS) were separated by liquid chromatography using a Shimadzu XR system (Shimadzu, Kyoto, Japan) 44 . PE and PS were then detected using an Orbitrap Elite mass spectrometer in full scan mode with a mass range of 400-1000 m/z at a target resolution of 240,000 (FWHM at m/z 400).…”

Section: Methodsmentioning

confidence: 99%

Non-canonical autophagy drives alternative ATG8 conjugation to phosphatidylserine

Durgan

Lystad

Sloan

et al. 2020

Preprint

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29 30 Autophagy is a fundamental catabolic process essential for development, 31 homeostasis and proper immune function 1 . During autophagy, a cascade of 32 ATG proteins target intracellular cargoes for lysosomal degradation and 33 recycling 2 . This pathway utilises a unique post-translational modification, the 34 conjugation of ATG8 proteins to phosphatidylethanolamine (PE) at 35 autophagosomes, which modulates cargo selection and maturation. 36 ATG8 lipidation also occurs during non-canonical autophagy, a parallel pathway 37 involving Single Membrane ATG8 Conjugation (SMAC) to endolysosomal 38compartments, which plays a key role in phagocytosis and other processes 3 . It 39 has been widely assumed that SMAC involves the same lipidation of ATG8 to 40 PE, but this has yet to be formally tested. Here, we show that ATG8 undergoes 41 alternative lipidation to phosphatidylserine (PS) during non-canonical 42 autophagy/SMAC. Using mass spectrometry, we find that activation of SMAC, 43 by pharmacological agents 4,5 , or during non-canonical autophagy processes such 44 as LC3-associated phagocytosis 6,7 and Influenza A virus infection 8 , induces the 45 covalent conjugation of ATG8 to PS, as well as PE. This alternative lipidation 46 event is dependent on the ATG16L1 WD40 domain, and occurs at PS enriched 47 endolysosomal membranes. Importantly, we find that the ATG8-PS and ATG8-48 PE adducts are differentially delipidated by isoforms of the ATG4 family, 49 indicating significant molecular distinctions and mechanisms between these two 50 species. 51Together, these results provide an important new insight into autophagy 52 signalling, revealing an alternative form of the hallmark ATG8-lipidation event, 53Main 60 61 A defining feature of autophagy is the lipidation of ATG8, a family of ubiquitin-like 62 proteins including mammalian LC3s (A/B/B2/C) and GABARAPs 63 (GABARAP/L1/L2) 9 . Nascent pro-ATG8 is first primed by a cysteine protease, 64 ATG4, to expose a conserved aromatic-Gly motif at its C-terminus 10 . A ubiquitin-65 like conjugation system, comprised of ATG7 (E1-like), ATG3 (E2-like) and 66 ATG16L1/ATG12/ATG5 (E3-like), then drives the covalent ligation of this glycine to 67 a lipid, phosphatidylethanolamine (PE), via an amide bond to its headgroup (Extended 68 Data Fig. 1a) 11,12 . This is a unique post-translational modification that recruits ATG8 69 to autophagosomal membranes, where it plays an important role in cargo loading and 70 autophagosome maturation 9,13 . The associated relocalisation of ATG8s, and the 71 characteristic protein bandshift between the unlipidated (ATG8-I) and lipidated 72 (ATG8-II) forms, are widely used to define and assay autophagy-related processes 73 14,15 . 74 75A second phospholipid, phosphatidylserine (PS), also bears an amino group in its 76 head moiety (Extended Data Fig. 1b), which can be conjugated to ATG8 in vitro 16 . 77However, in vivo, ATG8 lipidation is reported to occur exclusively to PE, in both 78 yeast 11 and mammalian cells 16 . The mechanism underlying cellular...

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“…Furthermore, in liver biopsies from HCV genotype 1b-infected patients, PER2 was almost exclusively localized to the nucleus, which is suggestive of an auto-inhibitory transcriptional feedback loop [79]. More recently, it was shown that the core-clock components BMAL1 and REV-ERBα act upon more steps in the HCV life cycle, including the entry of viral particles into hepatocytes and the replication of the viral RNA [89]. In fact, pharmacological activation of REV-ERB inhibited HCV entry, and genetic knockout of Bmal1 or overexpression/pharmacological activation of REV-ERB was able to counteract HCV replication by modulating the circadian expression of the liver-specific microRNA miR-122 with consequent derangements of signalling pathways involved in lipid metabolism [89].…”

Section: Epigenetic Mechanisms Underlying the Interaction Between Virmentioning

confidence: 96%

The Circadian Clock, the Immune System, and Viral Infections: The Intricate Relationship Between Biological Time and Host-Virus Interaction

et al. 2020

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Living beings spend their lives and carry out their daily activities interacting with environmental situations that present space-time variations and that involve contact with other life forms, which may behave as commensals or as invaders and/or parasites. The characteristics of the environment, as well as the processes that support the maintenance of life and that characterize the execution of activities of daily life generally present periodic variations, which are mostly synchronized with the light–dark cycle determined by Earth’s rotation on its axis. These rhythms with 24-h periodicity, defined as circadian, influence events linked to the interaction between hosts and hosted microorganisms and can dramatically determine the outcome of this interplay. As for the various pathological conditions resulting from host–microorganism interactions, a particularly interesting scenario concerns infections by viruses. When a viral agent enters the body, it alters the biological processes of the infected cells in order to favour its replication and to spread to various tissues. Though our knowledge concerning the mutual influence between the biological clock and viruses is still limited, recent studies start to unravel interesting aspects of the clock–virus molecular interplay. Three different aspects of this interplay are addressed in this mini-review and include the circadian regulation of both innate and adaptive immune systems, the impact of the biological clock on viral infection itself, and finally the putative perturbations that the virus may confer to the clock leading to its deregulation.

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The circadian clock components BMAL1 and REV-ERBα regulate flavivirus replication

Cited by 80 publications

References 66 publications

Cold induced chromatin compaction and nuclear retention of clock mRNAs resets the circadian rhythm

Cold induced chromatin compaction and nuclear retention of clock mRNAs resets the circadian rhythm

Non-canonical autophagy drives alternative ATG8 conjugation to phosphatidylserine

The Circadian Clock, the Immune System, and Viral Infections: The Intricate Relationship Between Biological Time and Host-Virus Interaction

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