Fig. 6: Model of the molecular pathway disrupted as a consequence of the UBLCP1 ASD mutation.
From: A novel autism-associated UBLCP1 mutation impacts proteasome regulation/activity
(Left) The activity and regulation of the proteasome under normal conditions. A transcription factor (TF) is released from the endoplasmic reticulum (ER) to the cytosol, where it is degraded by active proteasomes. With proteotoxic stress, the TF enters the nucleus and binds to antioxidant response element (ARE) core sequences found upstream of most proteasome subunit genes, including UBLCP1. These levels of gene transcription maintain a pool of free subunits from which proteasome assembly can rapidly be generated. In the nucleus, wild-type UBLCP1 (pink) restrains the assembly of the proteasome. Fully assembled proteasomes are translocated to the cytosol, where they are active. (Right) The activity and regulation of the proteasome in ASD patient-derived cells with the UBLCP1 (del g.158,710,261CAAAG > C) mutation. In the nucleus, the loss-of-function mutant UBLCP1 (peach) leads to an increase in proteasome assembly. A higher number of proteasomes are translocated to the cytosol, where they become active. This is reflected in increased protein degradation. The TF released from the ER is degraded, which leads to a decrease in the number of TF molecules entering the nucleus and a decrease in transcription levels of proteasome subunits and of UBLCP1.
