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

David Liang, Liping Jiang, Sameer Ahmed Bhat, Sonia Missiroli, Mariasole Perrone, Angela Lauriola, Ritika Adhikari, Anish Gudur, Zahra Vasi, Ian Ahearn, Daniele Guardavaccaro, Carlotta Giorgi, Mark Philips, Shafi Kuchay

Journal: Cell reports 2023;42(1):111999

PMID: 36662618

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Abstract

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 SCF. 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.

Address: Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, MBRB #1157, Chicago, IL 60607, USA.; Department of Medical Sciences, Section of Experimental Medicine, University of Ferrara, 44121 Ferrara, Italy.; Department of Biotechnology, University of Verona, 37134 Verona, Italy.; Department of Dermatology and Perlmutter Cancer Center, New York University Grossman School of Medicine, New York, NY 10016, USA.; Department of Medicine and Perlmutter Cancer Center, New York University Grossman School of Medicine, New York, NY 10016, USA.; Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, MBRB #1157, Chicago, IL 60607, USA. Electronic address: [email protected].

DOI: 10.1016/j.celrep.2023.111999

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MeSH Terms: F-Box Proteins, Calcium, Lipoylation, Ubiquitination, Lipids