The Importance of UBQLN2 Ubiquitylation for Its Turnover and Localization

TY - JOUR

T1 - The Importance of UBQLN2 Ubiquitylation for Its Turnover and Localization

AU - Grønbæk-Thygesen, Martin

AU - Kampmeyer, Caroline

AU - Eschger, Paula

AU - Tatham, Michael H.

AU - Arts, Marloes

AU - Hofmann, Kay

AU - Lindorff-Larsen, Kresten

AU - Boomsma, Wouter

AU - Hartmann-Petersen, Rasmus

N1 - Publisher Copyright: © 2025 American Chemical Society

PY - 2026/1/6

Y1 - 2026/1/6

N2 - UBQLN2 is a member of the UBL-UBA domain protein family that functions as extrinsic substrate receptors for the 26S proteasome. UBQLN2 has been shown to undergo phase separation in vitro. In cells, UBQLN2 forms condensates that may be of importance for tuning protein degradation via the ubiquitin-proteasome system and potentially of relevance for UBQLN2-linked amyotrophic lateral sclerosis (ALS). Here we show that UBQLN2 is ubiquitylated on lysine residues in the N-terminal UBL domain. The C-terminal region of UBQLN2 is lysine-depleted, and we show that introducing lysine residues in this region leads to its E6AP-dependent degradation. The UBL domain critically stabilizes UBQLN2 and protects it from proteasomal degradation. Fusion of ubiquitin to the UBQLN2 N-terminus stabilizes UBQLN2 and increases its propensity for locating in puncta, indicating that ubiquitylation of the UBQLN2 UBL domain regulates abundance and localization.

AB - UBQLN2 is a member of the UBL-UBA domain protein family that functions as extrinsic substrate receptors for the 26S proteasome. UBQLN2 has been shown to undergo phase separation in vitro. In cells, UBQLN2 forms condensates that may be of importance for tuning protein degradation via the ubiquitin-proteasome system and potentially of relevance for UBQLN2-linked amyotrophic lateral sclerosis (ALS). Here we show that UBQLN2 is ubiquitylated on lysine residues in the N-terminal UBL domain. The C-terminal region of UBQLN2 is lysine-depleted, and we show that introducing lysine residues in this region leads to its E6AP-dependent degradation. The UBL domain critically stabilizes UBQLN2 and protects it from proteasomal degradation. Fusion of ubiquitin to the UBQLN2 N-terminus stabilizes UBQLN2 and increases its propensity for locating in puncta, indicating that ubiquitylation of the UBQLN2 UBL domain regulates abundance and localization.

UR - https://www.scopus.com/pages/publications/105026564225

U2 - 10.1021/acs.biochem.5c00619

DO - 10.1021/acs.biochem.5c00619

M3 - Article

C2 - 41428212

AN - SCOPUS:105026564225

SN - 0006-2960

VL - 65

SP - 52

EP - 63

JO - Biochemistry

JF - Biochemistry

IS - 1

ER -