The Importance of UBQLN2 Ubiquitylation for Its Turnover and Localization

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.