A genome-wide CRISPR screen identifies DPM1 as a modifier of DPAGT1 deficiency and ER stress.
Partial loss-of-function mutations in glycosylation pathways underlie a set of rare diseases called Congenital Disorders of Glycosylation (CDGs). In particular, DPAGT1-CDG is caused by mutations in the gene encoding the first step in N-glycosylation, DPAGT1, and this disorder currently lacks effecti...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2022-09-01
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| Series: | PLoS Genetics |
| Online Access: | https://doi.org/10.1371/journal.pgen.1010430 |
| _version_ | 1828004345169313792 |
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| author | Hans M Dalton Raghuvir Viswanatha Roderick Brathwaite Jae Sophia Zuno Alexys R Berman Rebekah Rushforth Stephanie E Mohr Norbert Perrimon Clement Y Chow |
| author_facet | Hans M Dalton Raghuvir Viswanatha Roderick Brathwaite Jae Sophia Zuno Alexys R Berman Rebekah Rushforth Stephanie E Mohr Norbert Perrimon Clement Y Chow |
| author_sort | Hans M Dalton |
| collection | DOAJ |
| description | Partial loss-of-function mutations in glycosylation pathways underlie a set of rare diseases called Congenital Disorders of Glycosylation (CDGs). In particular, DPAGT1-CDG is caused by mutations in the gene encoding the first step in N-glycosylation, DPAGT1, and this disorder currently lacks effective therapies. To identify potential therapeutic targets for DPAGT1-CDG, we performed CRISPR knockout screens in Drosophila cells for genes associated with better survival and glycoprotein levels under DPAGT1 inhibition. We identified hundreds of candidate genes that may be of therapeutic benefit. Intriguingly, inhibition of the mannosyltransferase Dpm1, or its downstream glycosylation pathways, could rescue two in vivo models of DPAGT1 inhibition and ER stress, even though impairment of these pathways alone usually causes CDGs. While both in vivo models ostensibly cause cellular stress (through DPAGT1 inhibition or a misfolded protein), we found a novel difference in fructose metabolism that may indicate glycolysis as a modulator of DPAGT1-CDG. Our results provide new therapeutic targets for DPAGT1-CDG, include the unique finding of Dpm1-related pathways rescuing DPAGT1 inhibition, and reveal a novel interaction between fructose metabolism and ER stress. |
| first_indexed | 2024-04-10T07:13:17Z |
| format | Article |
| id | doaj.art-bbc74efb857641bd92e0108b5c183c6e |
| institution | Directory Open Access Journal |
| issn | 1553-7390 1553-7404 |
| language | English |
| last_indexed | 2024-04-10T07:13:17Z |
| publishDate | 2022-09-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj.art-bbc74efb857641bd92e0108b5c183c6e2023-02-26T05:31:22ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042022-09-01189e101043010.1371/journal.pgen.1010430A genome-wide CRISPR screen identifies DPM1 as a modifier of DPAGT1 deficiency and ER stress.Hans M DaltonRaghuvir ViswanathaRoderick BrathwaiteJae Sophia ZunoAlexys R BermanRebekah RushforthStephanie E MohrNorbert PerrimonClement Y ChowPartial loss-of-function mutations in glycosylation pathways underlie a set of rare diseases called Congenital Disorders of Glycosylation (CDGs). In particular, DPAGT1-CDG is caused by mutations in the gene encoding the first step in N-glycosylation, DPAGT1, and this disorder currently lacks effective therapies. To identify potential therapeutic targets for DPAGT1-CDG, we performed CRISPR knockout screens in Drosophila cells for genes associated with better survival and glycoprotein levels under DPAGT1 inhibition. We identified hundreds of candidate genes that may be of therapeutic benefit. Intriguingly, inhibition of the mannosyltransferase Dpm1, or its downstream glycosylation pathways, could rescue two in vivo models of DPAGT1 inhibition and ER stress, even though impairment of these pathways alone usually causes CDGs. While both in vivo models ostensibly cause cellular stress (through DPAGT1 inhibition or a misfolded protein), we found a novel difference in fructose metabolism that may indicate glycolysis as a modulator of DPAGT1-CDG. Our results provide new therapeutic targets for DPAGT1-CDG, include the unique finding of Dpm1-related pathways rescuing DPAGT1 inhibition, and reveal a novel interaction between fructose metabolism and ER stress.https://doi.org/10.1371/journal.pgen.1010430 |
| spellingShingle | Hans M Dalton Raghuvir Viswanatha Roderick Brathwaite Jae Sophia Zuno Alexys R Berman Rebekah Rushforth Stephanie E Mohr Norbert Perrimon Clement Y Chow A genome-wide CRISPR screen identifies DPM1 as a modifier of DPAGT1 deficiency and ER stress. PLoS Genetics |
| title | A genome-wide CRISPR screen identifies DPM1 as a modifier of DPAGT1 deficiency and ER stress. |
| title_full | A genome-wide CRISPR screen identifies DPM1 as a modifier of DPAGT1 deficiency and ER stress. |
| title_fullStr | A genome-wide CRISPR screen identifies DPM1 as a modifier of DPAGT1 deficiency and ER stress. |
| title_full_unstemmed | A genome-wide CRISPR screen identifies DPM1 as a modifier of DPAGT1 deficiency and ER stress. |
| title_short | A genome-wide CRISPR screen identifies DPM1 as a modifier of DPAGT1 deficiency and ER stress. |
| title_sort | genome wide crispr screen identifies dpm1 as a modifier of dpagt1 deficiency and er stress |
| url | https://doi.org/10.1371/journal.pgen.1010430 |
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