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- Title
Palmitoylated Sept8-204 modulates learning and anxiety by regulating filopodia arborization and actin dynamics.
- Authors
Liu, Huicong; Yan, Peipei; Wu, Can; Rao, Muding; Zhu, Jiangli; Lv, Luxian; Li, Wenqiang; Liang, Yinming; Qi, Shiqian; Lu, Kefeng; Kong, Eryan
- Abstract
Septin proteins are involved in diverse physiological functions, including the formation of specialized cytoskeletal structures. Septin 8 (Sept8) is implicated in spine morphogenesis and dendritic branching through palmitoylation. We explored the role and regulation of a Sept8 variant in human neural-like cells and in the mouse brain. We identified Sept8-204 as a brain-specific variant of Sept8 that was abundant in neurons and modified by palmitoylation, specifically at Cys469, Cys470, and Cys472. Sept8-204 palmitoylation was mediated by the palmitoyltransferase ZDHHC7 and was removed by the depalmitoylase PPT1. Palmitoylation of Sept8-204 bound to F-actin and induced cytoskeletal dynamics to promote the outgrowth of filopodia in N2a cells and the arborization of neurites in hippocampal neurons. In contrast, a Sept8-204 variant that could not be palmitoylated because of mutation of all three Cys residues (Sept8-204-3CA) lost its ability to bind F-actin, and expression of this mutant did not promote morphological changes. Genetic deletion of Sept8, Sept8-204, or Zdhhc7 caused deficits in learning and memory and promoted anxiety-like behaviors in mice. Our findings provide greater insight into the regulation of Sept8-204 by palmitoylation and its role in neuronal morphology and function in relation to cognition. Editor's summary: Palmitoylation regulates the stability and localization of proteins that are important for neuronal function. Liu et al. found that the palmitoylation of the synaptic protein Sept8-204 promoted morphological changes in hippocampal neurons associated with learning and memory. S-palmitoylation at three cysteine sites promoted the interaction of Sept8-204 with the actin cytoskeleton, enabling dendritic outgrowth and branching and promoting cognition in mice. Mice lacking Sept8-204 or the enzyme that mediates its palmitoylation had learning and memory deficits and showed anxiety-like behaviors. The findings deepen our understanding of this lipid modification in spine formation and cognition. —Leslie K. Ferrarelli
- Subjects
FILOPODIA; DENDRITIC spines; ACTIN; PALMITOYLATION; CYTOSKELETON; MEMORY disorders
- Publication
Science Signaling, 2023, Vol 16, Issue 814, p1
- ISSN
1945-0877
- Publication type
Article
- DOI
10.1126/scisignal.adi8645