In HD, the protein HOIP interacts with mHtt by promoting linear polyubiquitin formation on mHtt. Silencing HOIP reduces mHtt ubiquitination, increasing interaction between mHtt and the transcription factor Sp1, resulting in transcriptional dysregulation, aggregation, and proteotoxicity. This effect is counteracted by silencing OTULIN, a deubiquitinase that hydrolyzes linear polyubiquitin. The polyQ expansion in mHtt influences its ubiquitination, affecting degradation and aggregation. Here, SP1 is linked to Huntington disease.