Genetic alteration of human MYH6 is mimicked by SARS-CoV-2 polyprotein: mapping viral variants of cardiac interest.

Acute cardiac injury has been observed in a subset of COVID-19 patients, but the molecular basis for this clinical phenotype is unknown. It has been hypothesized that molecular mimicry may play a role in triggering an autoimmune inflammatory reaction in some individuals after SARS-CoV-2 infection. Here we investigate if linear peptides contained in proteins that are primarily expressed in the heart also occur in the SARS-CoV-2 proteome. Specifically, we compared the library of 136,704 8-mer peptides from 144 human proteins (including splicing variants) to 9926 8-mers from all the viral proteins in the reference SARS-CoV-2 proteome. No 8-mers were exactly identical between the reference human proteome and the reference SARS-CoV-2 proteome. However, there were 45 8-mers that differed by only one amino acid when compared to the reference SARS-CoV-2 proteome. Interestingly, analysis of protein-coding mutations from 141,456 individuals showed that one of these 8-mers from the SARS-CoV-2 Replicase polyprotein 1a/1ab (KIALKGGK) is identical to an MYH6 peptide encoded by the c.5410 C > A (Q1804K) genetic variation, which has been observed at low prevalence in Africans/African Americans (0.08%), East Asians (0.3%), South Asians (0.06%), and Latino/Admixed Americans (0.003%). Furthermore, analysis of 4.85 million SARS-CoV-2 genomes from over 200 countries shows that viral evolution has already resulted in 20 additional 8-mer peptides that are identical to human heart-enriched proteins encoded by reference sequences or genetic variants. Whether such mimicry contributes to cardiac inflammation during or after COVID-19 illness warrants further experimental evaluation. We suggest that SARS-CoV-2 variants harboring peptides identical to human cardiac proteins should be investigated as "viral variants of cardiac interest".

Biliverdin during Xenopus laevis oogenesis and early embryogenesis.

Biliverdin is required for Xenopus laevis embryo dorsal axis formation. When the tetrapyrrole is inactivated by phototransforming it with ultraviolet light prior to the first division, the embryo fails to synthesize dorsal mRNAs, such as goosecoid or chordin, yet forms increased amounts of ventral transcripts, such as Vent 1, and, consequently, develops ventralized morphology. Here we describe the metabolism of biliverdin during oogenesis and early embryogenesis. Estrogen induces frog hepatocytes to synthesize biliverdin and vitelogenin. The two molecules form a complex that is secreted into and transported in the plasma to be taken up by the oocyte as it matures through its six stages of oogenesis. In the oocyte, the biliverdin-vitellogenin complex is processed and stored in the yolk platelets. In these organelles, biliverdin is associated entirely with the lipovitellin domain of the processed vitellogenin. Once the egg is fertilized, its biliverdin content decreases over a 5-6 h period to participate in the chemical machinery required for dorsal axis formation. This participation must be initiated during the period encompassing the first embryonic mitosis. The results describe the pathway that generates, transports, and stores biliverdin as part of oogenesis, define the time course for its utilization after fertilization, and link biliverdin to the metabolism of the phosphoglycolipometalloprotein, vitellogenin.

A role for biliverdin IXalpha in dorsal axis development of Xenopus laevis embryos.

The determinants of Xenopus laevis embryos that act before their first cell division are mandatory for the formation of mRNas required to establish the dorsal axis. Although their chemical identities are unknown, a number of their properties have long been recognized. One of the determinants is present in the cytoplasm and is sensitive to UV light. Thus, exposing stage 1 embryos to either standard 254-nm or, as shown here, to 366-nm UV light during the 0.3-0.4 time fraction of their first cycle inactivates the cytoplasmic determinant. As a consequence, both types of irradiated embryos fail to express dorsal markers, e.g., goosecoid and chordin, without affecting formation of ventral markers, e.g., Vent-1. The developmental outcome is dorsal axis-deficient morphology. We report here that biliverdin IXalpha, a normal constituent of cytoplasmic yolk platelets, is photo-transformed by irradiation with either 254- or 366-nm UV light and that the transformation triggers the dorsal axis deficiency. When the 254- or 366-nm UV-irradiated embryos, fated to dorsal axis deficiency, are incubated solely with microM amounts of biliverdin, they recover and form the axis. In contrast, incubation with either in vitro photo-transformed biliverdin or biliverdin IXalpha dimethyl ester does not induce recovery. The results define an approach to produce dorsal axis-deficient embryos by photo-transforming its biliverdin by irradiation with 366-nm UV light and identify an unsuspected role for biliverdin IXalpha in X. laevis embryogenesis.