A Degron‐Like Regulatory Region in the <scp>ASXL1</scp> C‐Terminal Domain Mediates <scp>HCF</scp> ‐1–Dependent Regulation of Protein Stability

Somatic mutations in the ASXL1 gene, frequently found in myeloid malignancies, often generate C-terminal truncations and lead to abnormal protein accumulation. However, the molecular mechanisms regulating ASXL1 protein stability remain incompletely understood. Using a P2A peptide-based dual-reporter system, we demonstrate that truncated ASXL1 lacking the C-terminal domain (CTD) exhibits enhanced stability due to reduced ubiquitin-proteasome-mediated degradation. Dissection of the CTD revealed both destabilizing (IDR-1) and stabilizing (PEST) elements, indicating a complex sequence-encoded regulation of ASXL1 turnover. We identify Host Cell Factor 1 (HCF-1) as a cofactor that binds to the C-terminal ~200 amino acids of ASXL1 and promotes its turnover in a proteasome-dependent manner. Deletion of this region abrogates HCF-1 binding and stabilizes ASXL1. Although their binding sites are spatially distinct, HCF-1 and BAP1 show reciprocal antagonism in association with ASXL1, consistent with indirect coupling in complex assembly. Our findings identify a degron-like regulatory region within the ASXL1 CTD that integrates structural disorder and cofactor interactions to fine-tune protein stability, providing mechanistic insight into how truncating mutations dysregulate ASXL1 homeostasis.