Ubiquitylation of the ER-Shaping Protein Lunapark via the CRL3KLHL12 Ubiquitin Ligase Complex

Abstract

Highlights d A proteomic approach to identify CRL substrates ubiquitylated at cellular membranes d The ER shaping protein Lunapark is ubiquitylated by the CRL3 KLHL12 ubiquitin ligase d Lunapark binds mTOR and its ubiquitylation affects lysosomal recruitment of mTORC1 d Inhibition of Lunapark ubiquitylation leads to neurodevelopmental defects

Phosphorylation and Stabilization of PIN1 by JNK Promote Intrahepatic Cholangiocarcinoma Growth

“…D). Similar results were obtained when a mutant form of ubiquitin (UbK0), which allows only mono‐ubiquitination due to the lack of lysine residues, ( 38 ) was used instead of WT ubiquitin (Supporting Fig. E).…”

Co-adaptor driven assembly of a CUL3 E3 ligase complex

“…A recent study showed that LNP uses a Pro-rich motif to bind KLHL12 (Yuniati et al, 2020), an observation that we confirmed (Figure 4A). PEF1 possesses a similar Pro-rich sequence in its amino-terminal domain, which is required for recognition by KLHL12 (Figure 4A) and for restoring CUL3 KLHL12 assembly in DPEF1 cells (Figure 4B).…”

“…At the same time, PEF1 deletion promoted the interaction of KLHL12 with Lunapark (LNP) (Figure 2A), an ER membrane protein that was not detected in CUL3 KLHL12 -PEF1-ALG2 enzymes (Figure 2B). While we and others had noted LNP in complexes of overexpressed KLHL12 (McGourty et al, 2016;Yuniati et al, 2020), these findings suggested that endogenous LNP preferentially interacts with KLHL12 molecules that are not engaged with co-adaptor or CUL3.…”

Nodal modulator (NOMO) is required to sustain endoplasmic reticulum morphology

“…5). While Atlastins, Rtn3, and Lunapark have been previously linked to autophagy (49)(50)(51)(52), the connection of NOMO1 and Climp63 to the autophagic/lysosomal route is to our knowledge underexplored and warrants closer scrutiny in the future.…”