UBQLN1

Description

The UBQLN1 (ubiquilin 1) is a protein-coding gene located on chromosome 9.

Ubiquilin-1 is a protein encoded by the UBQLN1 gene in humans. It contains two domains: an N-terminal ubiquitin-like domain and a C-terminal ubiquitin-associated domain. Ubiquilin-1 is associated with protein degradation and aggregation of misfolded proteins, potentially playing a role in neurodegenerative diseases. It acts as a molecular chaperone for amyloid precursor protein (APP), a protein linked to Alzheimer's disease. Ubiquilin-1 was first identified through its interactions with presenilins. Two transcript variants encoding different isoforms have been found for this gene. Human UBQLN1 shares significant similarity with related ubiquilins, including UBQLN2 and UBQLN4.

UBQLN1 plays a key role in regulating protein degradation pathways, including the ubiquitin-proteasome system (UPS), autophagy, and the endoplasmic reticulum-associated protein degradation (ERAD) pathway. It facilitates the breakdown of misfolded or accumulated proteins by targeting them to the proteasome. This process involves binding to polyubiquitin chains via its UBA domain and interacting with proteasome subunits via its ubiquitin-like domain. UBQLN1 also participates in ERAD by interacting with ER-localized proteins such as UBXN4, VCP, and HERPUD1, acting as a bridge between polyubiquitinated ERAD substrates and the proteasome. Moreover, UBQLN1 is involved in the regulation of macroautophagy and autophagosome formation. It's essential for the maturation of LC3, an autophagy-related protein, and may contribute to the maturation of autophagosomes into autolysosomes by mediating autophagosome-lysosome fusion. UBQLN1 negatively regulates the TICAM1/TRIF-dependent toll-like receptor signaling pathway by reducing the abundance of TICAM1 through the autophagic pathway. It promotes the ubiquitination and lysosomal degradation of ORAI1, ultimately downregulating ORAI1-mediated calcium mobilization. In addition, UBQLN1 suppresses the maturation and proteasomal degradation of amyloid beta A4 protein (A4) by stimulating K63-linked polyubiquitination. It delays A4 maturation by sequestering it in the Golgi apparatus and preventing its transport to the cell surface for further processing. It also ubiquitinates BCL2L10, thereby stabilizing its protein abundance. UBQLN1 plays a role in the unfolded protein response (UPR) by attenuating the induction of UPR-inducible genes, DDTI3/CHOP, HSPA5, and PDIA2 during ER stress. Notably, it plays a crucial role in regulating PSEN1 levels by directing its accumulation to aggresomes, which are then removed from cells by autophagocytosis.

UBQLN1 is also known as DA41, DSK2, PLIC-1, UBQN, XDRP1.

Associated Diseases

WES Whole Exome Sequencing