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The Global Phosphorylation Landscape of SARS-CoV-2 Infection

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) belongs to the enveloped positive-sense RNA viruses. In the ongoing pandemic no vaccine has been approved as of yet. The Phosphorylation Landscape of SARS-CoV-2 Infection presented here is a step towards a deeper understanding of virus-host relationship and vaccine development.1

During a COVID-19 infection both, host and viral proteins, undergo major changes in phosphorylation. The virus tries to alter activities of e.g. kinases in order to influence cellular signaling to its benefits. The map on the left is based on the SARS-CoV-2 virus-host protein-protein interaction map of Gordon et al.2 and shows 40 human proteins which are significantly differentially phosphorylated across infection at least two time points. Viral proteins are shown as green diamonds. Interacting human proteins are shown as gray or respectively dark grey circles . PHs emanate from human proteins, colored by change compared with uninfected control samples (red, increase; blue, decrease) at each time point (0, 2, 4, 8, 12, and 24 h after infection) in a clockwise fashion.

The SARS-CoV-2 N protein is known to interact with several RNA-processing proteins that are differentially phosphorylated during infection, including LARP1 and RRP9. Here LARP1 phosphorylation decreases on several sites, which is known to consequently increase LARP1 affinity for 3' untranslated regions (UTRs) of mRNAs encoding ribosomal proteins, driving inhibition of human protein synthesis.3 In addition, Nsp8 interacts with LARP7 and MEPCE which are important regulators of RNA polymerase II-mediated transcription elongation as part of the 7SK small nuclear ribonucleoprotein particle (snRNP) complex. Their phosphorylation may influence positive transcription elongation factor b (PTEFb [CDK9]) and transcriptional regulation of the virus.4

10 of the 40 interacting proteins are kinases, a decrease in activity for MARK2 and PRKACA were observed while CK2 shows increased activity. The changes in kinase activity offer insights into the biology of viral infection and possible attack points to fight an infection. Therefore kinases are predestined as drug targets and further research may lead to  development of novel therapeutics relevant for future virus pandemics.

SARS-CoV-2 Structural Proteins: SARS-CoV-2 Spike Protein, SARS-CoV-2 N Protein, SARS-CoV-2 E Protein, SARS-CoV-2 M Protein,

SARS-CoV Viral Proteins: , , , , , , ,

All SARS-CoV-2 Non-Structural Proteins: SARS-CoV-2 Non-Structural Proteins

SARS-CoV-2 Antibodies: anti-SARS-CoV-2 Antibodies

References:

  1.  Bouhaddou et al.The Global Phosphorylation Landscape of SARS-CoV-2 Infection, Cell (2020), doi.org/10.1016/j.cell.2020.06.034
  2. David E. Gordon, Gwendolyn M. Jang, Mehdi Bouhaddou, Jiewei Xu, Kirsten Obernier, Matthew J. O’Meara, Jeffrey Z. Guo, Danielle L. Swaney, Tia A. Tummino, Ruth Huettenhain, Robyn M. Kaake, Alicia L. Richards, Beril Tutuncuoglu, Helene Foussard, Jyoti Batra, N. J. K. A SARS-CoV-2-Human Protein-Protein Interaction Map Reveals Drug Targets and Potential Drug Repurposing. Nature. (2020).
  3. Hong, S., Freeberg, M.A., Han, T., Kamath, A., Yao, Y., Fukuda, T., Suzuki, T., Kim, J.K., and Inoki, K. . LARP1 functions as a molecular switch for mTORC1-mediated translation of an essential class of mRNAs. (2017) eLife 6, e25237.
  4. Mbonye, U.R., Wang, B., Gokulrangan, G., Chance, M.R., and Karn, J. . Phosphorylation of HEXIM1 at Tyr271 and Tyr274 Promotes Release of PTEFb from the 7SK snRNP Complex and Enhances Proviral HIV Gene Expression. Proteomics 15, 2078–2086. (2015)

SARS-CoV-2 Virus-Human Interacting Proteins

LARP1 (La Ribonucleoprotein Domain Family, Member 1):

MARK1 (MAP/microtubule Affinity-Regulating Kinase 1):

MARK2 - MAP/microtubule Affinity-Regulating Kinase 2:

PRKACA (Protein Kinase A, alpha):

PRKAR2A - Protein Kinase, CAMP-Dependent, Regulatory, Type II, alpha:

PRKAR2B - Protein Kinase, CAMP-Dependent, Regulatory, Type II, beta:

RRP9 - Ribosomal RNA Processing 9, Small Subunit (SSU) Processome Component, Homolog (Yeast):

APOL2 - Apolipoprotein L 2:

ATP13A3 (ATPase Type 13A3):

BRD2 (Bromodomain Containing 2):

CENPF (Centromere Protein F):

CCL11 (Chemokine (C-C Motif) Ligand 11):

CCL13 - Chemokine (C-C Motif) Ligand 13:

CCL2 - Chemokine (C-C Motif) Ligand 2:

CCL20 (Chemokine (C-C Motif) Ligand 20):

CLCC1 - Chloride Channel CLIC-Like 1:

CIT (Citron (Rho-Interacting, serine/threonine Kinase 21)):

CCDC86 - Coiled-Coil Domain Containing 86:

CRTC3 (CREB Regulated Transcription Coactivator 3):

DNMT1 - DNA (Cytosine-5)-Methyltransferase 1:

ERC1 (ELKS/RAB6-Interacting/CAST Family Member 1):

HECTD1 (HECT Domain Containing 1):

HDAC2 - Histone Deacetylase 2:

LARP4B (La Ribonucleoprotein Domain Family, Member 4B):

LARP7 (La Ribonucleoprotein Domain Family, Member 7):

MPHOSPH10 - M-Phase phosphoprotein 10 (U3 Small Nucleolar Ribonucleoprotein):

MAP7D1 (MAP7 Domain Containing 1):

MEPCE (Methylphosphate Capping Enzyme):

MIB1 - Mindbomb E3 Ubiquitin Protein Ligase 1:

MYCBP2 (MYC Binding Protein 2):

NKAP (NFKB Activating Protein):

NEK9 - NIMA (Never in Mitosis Gene A)- Related Kinase 9:

NUP210 (Nucleoporin 210kDa):

NUP214 (Nucleoporin 214kDa):

PKP2 - Plakophilin 2:

PLEKHA5 (Pleckstrin Homology Domain Containing, Family A Member 5):

SUN2 (Sad1 and UNC84 Domain Containing 2):

SNIP1 (Smad Nuclear Interacting Protein 1):

STOML2 (Stomatin (EPB72)-Like 2):

TOR1AIP1 (Torsin A Interacting Protein 1):

UBAP2L (Ubiquitin Associated Protein 2-Like):

ZC3H18 (Zinc Finger CCCH-Type Containing 18):

ZDHHC5 (Zinc Finger, DHHC-Type Containing 5):

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