Since becoming a member of NIH, I’ve held plenty of totally different management positions. However there may be one place that fortunately has remained fixed for me: lab chief. I run my very own analysis laboratory at NIH’s Nationwide Institute of Dental and Craniofacial Analysis (NIDCR).
My lab research a biochemical course of referred to as O-glycosylation. It’s basic to life and interesting to review. Our cells are sometimes adorned with quite a lot of carbohydrate sugars. O-glycosylation refers back to the biochemical course of by means of which these sugar molecules, both discovered on the cell floor or secreted, get added to proteins. The presence or absence of those sugars on sure proteins performs basic roles in regular tissue growth and first-line human immunity. It is also related to varied ailments, together with most cancers.
Our lab just lately joined a group of NIH scientists led by my NIDCR colleague Kelly Ten Hagen to reveal how O-glycosylation can affect SARS-CoV-2, the coronavirus that causes COVID-19, and its potential to fuse to cells, which is a key step in infecting them. In actual fact, our information, revealed within the journal Proceedings of the Nationwide Academy of Sciences, point out that some variants, appear to have mutated to use the method to their benefit .
The work builds on the virus’s reliance on the spike proteins that crown its outer floor to connect to human cells. As soon as there, the spike protein have to be activated to fuse and launch an an infection. That occurs when enzymes produced by our personal cells make a collection of cuts, or cleavages, to the spike protein.
The primary minimize comes from an enzyme referred to as furin. We and others had earlier proof that O-glycosylation can have an effect on the way in which furin makes these cuts. That bought us pondering: May O-glycosylation affect the interplay between furin and the spike protein? The furin cleavage space of the viral spike was certainly adorned with sugars, and their presence or absence would possibly affect spike activation by furin.
We additionally seen the Alpha and Delta variants carry a mutation that removes the amino acid proline in a selected spot. That was intriguing as a result of we knew from earlier work that enzymes referred to as GALNTs, that are liable for including cumbersome sugar molecules to proteins, want prolines close to O-glycosylation websites.
It additionally advised that lack of proline within the new variants might imply decreased O-glycosylation, which could then affect the diploma of furin cleavage and SARS-CoV-2’s potential to enter cells. I ought to be aware that the latest Omicron variant was not examined within the present examine.
After detailed research in fruit fly and mammalian cells, we demonstrated within the unique SARS-CoV-2 virus that O-glycosylation of the spike protein decreases furin cleavage. Additional experiments then confirmed that the GALNT1 enzyme provides sugars to the spike protein and this addition limits the power of furin to make the wanted cuts and activate the spike protein.
Importantly, the spike protein change discovered within the Alpha and Delta variants lowers GALNT1 exercise, making it simpler for furin to begin its activating cuts. It means that glycosylation of the viral spike by GALNT1 could restrict an infection with the unique virus, and that the Alpha and Delta variant mutation at the least partially overcomes this impact, to doubtlessly make the virus extra infectious.
Constructing on these research, our groups appeared for proof of GALNT1 within the respiratory tracts of wholesome human volunteers. We discovered that the enzyme is certainly abundantly expressed in these cells. Apparently, those self same cells additionally specific the ACE2 receptor, which SARS-CoV-2 relies on to contaminate human cells.
It’s additionally value noting right here that the Omicron variant carries the exact same spike mutation that we studied in Alpha and Delta. Omicron additionally has one other close by change that may additional alter O-glycosylation and cleavage of the spike protein by furin. The Ten Hagen lab is wanting into these results in learn the way this area in Omicron impacts spike glycosylation and, in the end, the power of this devastating virus to contaminate human cells and unfold.
 Furin cleavage of the SARS-CoV-2 spike is modulated by O-glycosylation. Zhang L, Mann M, Syed Z, Reynolds HM, Tian E, Samara NL, Zeldin DC, Tabak LA, Ten Hagen KG. PNAS. 2021 Nov 23;118(47).
COVID-19 Research (NIH)
Kelly Ten Hagen (Nationwide Institute of Dental and Craniofacial Analysis/NIH)
Lawrence Tabak (NIDCR)
NIH Assist: Nationwide Institute of Dental and Craniofacial Analysis