Palmitoylation and PDE6δ regulate membrane-compartment-specific substrate ubiquitylation and degradation.

Substrate degradation by the ubiquitin proteasome system (UPS) in specific membrane compartments remains elusive. Here, we show that the interplay of two lipid modifications and PDE6δ regulates compartmental substrate targeting via the SCFFBXL2. FBXL2 is palmitoylated in a prenylation-dependent manner on cysteines 417 and 419 juxtaposed to the CaaX motif. Palmitoylation/depalmitoylation regulates its subcellular trafficking for substrate engagement and degradation. To control its subcellular distribution, lipid-modified FBXL2 interacts with PDE6δ. Perturbing the equilibrium between FBXL2 and PDE6δ disrupts the delivery of FBXL2 to all membrane compartments, whereas depalmitoylated FBXL2 is enriched on the endoplasmic reticulum (ER). Depalmitoylated FBXL2(C417S/C419S) promotes the degradation of IP3R3 at the ER, inhibits IP3R3-dependent mitochondrial calcium overload, and counteracts calcium-dependent cell death upon oxidative stress. In contrast, disrupting the PDE6δ-FBXL2 equilibrium has the opposite effect. These findings describe a mechanism underlying spatially-restricted substrate degradation and suggest that inhibition of FBXL2 palmitoylation and/or binding to PDE6δ may offer therapeutic benefits.

Liang D ，Jiang L ，Bhat SA ，Missiroli S ，Perrone M ，Lauriola A ，Adhikari R ，Gudur A ，Vasi Z ，Ahearn I ，Guardavaccaro D ，Giorgi C ，Philips M ，Kuchay S ... -  《Cell Reports》

PTEN counteracts FBXL2 to promote IP3R3- and Ca(2+)-mediated apoptosis limiting tumour growth.

Kuchay S ，Giorgi C ，Simoneschi D ，Pagan J ，Missiroli S ，Saraf A ，Florens L ，Washburn MP ，Collazo-Lorduy A ，Castillo-Martin M ，Cordon-Cardo C ，Sebti SM ，Pinton P ，Pagano M ... -  《-》

FBXL2- and PTPL1-mediated degradation of p110-free p85β regulatory subunit controls the PI(3)K signalling cascade.

Kuchay S ，Duan S ，Schenkein E ，Peschiaroli A ，Saraf A ，Florens L ，Washburn MP ，Pagano M ... -  《-》

Calmodulin antagonizes a calcium-activated SCF ubiquitin E3 ligase subunit, FBXL2, to regulate surfactant homeostasis.

Chen BB ，Coon TA ，Glasser JR ，Mallampalli RK ... -  《-》

F-box protein FBXL2 inhibits gastric cancer proliferation by ubiquitin-mediated degradation of forkhead box M1.

F-box/LRR-repeat protein 2 (FBXL2), a component of Skp-Cullin-F box (SCF) ubiquitin E3 ligase, has been shown to inhibit tumorigenesis by targeting and ubiquitinating several oncoproteins. However, its role in gastric cancer remains poorly understood. Here, by tandem mass spectrometry, we show that FBXL2 interacts with forkhead box M1 (FoxM1) transcription factor. As a result, FBXL2 promotes ubiquitination and degradation of FoxM1 in gastric cancer cells. Furthermore, overexpression of FBXL2 inhibits, while its deficiency promotes cell proliferation and invasion. Expression levels of cell-cycle regulators (Cdc25B and p27), which are down-stream target effectors of FoxM1, are also regulated by FBXL2. Therefore, our results uncover a previous unknown network involving FBXL2 and FoxM1 in the regulation of gastric cancer growth.

Li LQ ，Pan D ，Chen H ，Zhang L ，Xie WJ ... -  《-》