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NGLY1 removes N-linked glycans from glycoproteins in the cytoplasm and is thought to help clear misfolded proteins from the endoplasmic reticulum (ER) through the ER associated degradation (ERAD) pathway. Despite this, the physiological significance of NGLY1 in ERAD is not understood. The best characterized substrate of NGLY1 is NRF1, a transcription factor that upregulates proteasome expression and the proteasome bounce-back response. We previously performed a genetic modifier screen using a <jats:italic><jats:italic>Drosophila<\/jats:italic><\/jats:italic> model of NGLY1 deficiency and identified potential modifiers that alter the lethality of the model. We identified two protein-coding variants in <jats:italic><jats:italic>Hrd3<\/jats:italic><\/jats:italic>\/<jats:italic>SEL1L<\/jats:italic>: <jats:italic><jats:italic>S780P<\/jats:italic><\/jats:italic> and <jats:italic>\u0394806\u2013809<\/jats:italic>. Both variants are localized to the SEL1L cytoplasmic tail, an uncharacterized domain. SEL1L is a component of the ERAD complex that retrotranslocates misfolded proteins from the ER to the cytoplasm for degradation. We used CRISPR to generate fly lines carrying these <jats:italic>SEL1L<\/jats:italic> variants in a common genetic background and tested them with our model of NGLY1 deficiency. Validating our previous screen, the <jats:italic>SEL1L<\/jats:italic><jats:sup><jats:italic>S780P<\/jats:italic><\/jats:sup> and <jats:italic>SEL1L<\/jats:italic><jats:sup><jats:italic>\u0394806-809<\/jats:italic><\/jats:sup> variants increased the survival of the NGLY1 deficiency model, compared to the <jats:italic>SEL1L<\/jats:italic><jats:sup><jats:italic>S780<\/jats:italic><\/jats:sup> variant. To determine how these <jats:italic>SEL1L<\/jats:italic> variants were modifying lethality in NGLY1 deficiency, we interrogated the ERAD and NRF1 signaling pathways. We found that the <jats:italic>SEL1L<\/jats:italic><jats:sup><jats:italic>S780P<\/jats:italic><\/jats:sup> and <jats:italic>SEL1L<\/jats:italic><jats:sup><jats:italic>\u0394806-809<\/jats:italic><\/jats:sup> variants improve resistance to ER stress, with enhanced ERAD function as a likely contributing mechanism. This effect depends on NGLY1 activity, further implicating NGLY1 in general ERAD function. We also found that, in heterozygous <jats:italic>NGLY1<\/jats:italic> null flies, these variants protect against some defects like increased lethality caused by proteasome inhibition. These results provide new insights into the role of SEL1L in the disease pathogenesis of NGLY1 deficiency. <jats:italic>SEL1L<\/jats:italic> is a strong candidate modifier gene in patients, where variability in presentation is common.<\/jats:p>","DOI":"10.1371\/journal.pgen.1011823","type":"journal-article","created":{"date-parts":[[2025,8,7]],"date-time":"2025-08-07T17:51:12Z","timestamp":1754589072000},"page":"e1011823","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":2,"title":["Natural SEL1L variants rescue a model of NGLY1 deficiency and modify ERAD function and proteasome sensitivity"],"prefix":"10.1371","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3420-3693","authenticated-orcid":true,"given":"Travis 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