UBQLN2

Description

The UBQLN2 (ubiquilin 2) is a protein-coding gene located on chromosome X.

Ubiquilin-2 is a protein that in humans is encoded by the UBQLN2 gene. This gene encodes a ubiquitin-like protein (ubiquilin) that shares high degree of similarity with related products in yeast, rat and frog. Ubiquilins contain a N-terminal ubiquitin-like domain and a C-terminal ubiquitin-associated domain. They physically associate with both proteasomes and ubiquitin ligases, and are thus thought to functionally link the ubiquitination machinery to the proteasome to effect in vivo protein degradation. This ubiquilin has also been shown to bind the ATPase domain of the Hsp70-like Hspa13 (Stch) protein. Human UBQLN2 shares a high degree of similarity with related ubiquilins including UBQLN1 and UBQLN4. In a small proportion of familial amyotrophic lateral sclerosis (fALS), the UBQLN2 gene is mutated, causing formation of a non-functional Ubiquilin 2 enzyme. This non-functioning enzyme leads to the accumulation of ubiquinated proteins in the lower motor neurons and upper corticospinal motor neurons, due to the fact that ubiquilin 2 normally degrades these ubiquinated proteins, but cannot if the ALS mutation is present. The same accumulations occur in patients without UBQLN2 mutations, but with mutations in other genes, including TDP-43 and C9ORF72.

Ubiquilin-2 (UBQLN2) plays a crucial role in regulating various protein degradation pathways, including the ubiquitin-proteasome system (UPS), autophagy, and the endoplasmic reticulum-associated protein degradation (ERAD) pathway. It facilitates the targeting of misfolded or accumulated proteins to the proteasome for degradation by binding to their polyubiquitin chains through its UBA domain and interacting with proteasome subunits through its ubiquitin-like domain. UBQLN2 also participates in the ERAD pathway by interacting with ER-localized proteins FAF2/UBXD8 and HERPUD1, potentially bridging polyubiquitinated ERAD substrates with the proteasome. Furthermore, UBQLN2 regulates macroautophagy and autophagosome formation, being essential for the maturation of the autophagy-related protein LC3 from its cytosolic form (LC3-I) to its membrane-bound form (LC3-II). It may contribute to the maturation of autophagosomes into autolysosomes by mediating autophagosome-lysosome fusion. Additionally, UBQLN2 negatively regulates the endocytosis of GPCR receptors, AVPR2 and ADRB2, by reducing the rate at which receptor-arrestin complexes accumulate in clathrin-coated pits (CCPs).

UBQLN2 is also known as ALS15, CHAP1, DSK2, HRIHFB2157, N4BP4, PLIC2.

Associated Diseases

• Amyotrophic lateral sclerosis 15 with or without frontotemporal dementia
• Amyotrophic lateral sclerosis