Proposed mechanism (IMAGE) Tokyo Metropolitan Institute of Medical Science Caption A schematic model of the mechanism of proteasome dysfunction by FBS2 in NGLY1 deficiency. FBS2 induces cellular toxicity in the absence of NGLY by two steps. First, FBS2 ubiquitinates misfolded glycoprotein substrates. Ubiquitinated glycoproteins recruited to the proteasome can strongly inhibit the proteasome activity, because of the presence of N-glycans. Accumulation of ubiquitinated glycoproteins results in the inhibition of the proteasome. Cells sense the inhibition of the proteasome, they try to induce transcriptional activation of proteasome subunits by active NRF1. But FBS2 suppresses by inhibiting nuclear import of NRF1. Moreover, induced NRF1 also causes proteasome dysfunction as the ubiquitinated glycoprotein substrates. Credit TMIMS Usage Restrictions None License Licensed content Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.