Monoubiquitination Promotes Calpain Cleavage of the Protein Phosphatase 2A (PP2A) Regulatory Subunit α4, Altering PP2A Stability and Microtubule-associated Protein Phosphorylation

• Published in: The Journal of biological chemistry Vol. 287; no. 29; pp. 24207 - 24215
• Main Authors: Watkins, Guy R., Wang, Ning, Mazalouskas, Matthew D., Gomez, Rey J., Guthrie, Chris R., Kraemer, Brian C., Schweiger, Susann, Spiller, Benjamin W., Wadzinski, Brian E.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 13.07.2012; American Society for Biochemistry and Molecular Biology
• Subjects: alpha4; Alzheimer Disease; Blotting, Western; Cell Line; E3 Ubiquitin Ligase; Humans; Immunoprecipitation; Mass Spectrometry; Microtubule-associated Protein; Microtubule-Associated Proteins - genetics; Microtubule-Associated Proteins - metabolism; Phosphatase; Phosphorylation - genetics; Phosphorylation - physiology; PP2A; Protein Phosphatase 2 - genetics; Protein Phosphatase 2 - metabolism; Protein Stability; Signal Transduction; Ubiquitination; Ubiquitination - genetics; Ubiquitination - physiology; E3 Ubiquitin Ligase; Ubiquitination; Microtubule-associated Protein; PP2A; alpha4; Alzheimer Disease; Phosphatase
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M112.368613

Multiple neurodegenerative disorders are linked to aberrant phosphorylation of microtubule-associated proteins (MAPs). Protein phosphatase 2A (PP2A) is the major MAP phosphatase; however, little is known about its regulation at microtubules. α4 binds the PP2A catalytic subunit (PP2Ac) and the microtubule-associated E3 ubiquitin ligase MID1, and through unknown mechanisms can both reduce and enhance PP2Ac stability. We show MID1-dependent monoubiquitination of α4 triggers calpain-mediated cleavage and switches α4's activity from protective to destructive, resulting in increased Tau phosphorylation. This regulatory mechanism appears important in MAP-dependent pathologies as levels of cleaved α4 are decreased in Opitz syndrome and increased in Alzheimer disease, disorders characterized by MAP hypophosphorylation and hyperphosphorylation, respectively. These findings indicate that regulated inter-domain cleavage controls the dual functions of α4, and dysregulation of α4 cleavage may contribute to Opitz syndrome and Alzheimer disease. Background: α4 binds to the PP2A catalytic subunit and the microtubule-associated E3 ligase MID1. Results: MID1-dependent monoubiquitination promotes calpain-mediated cleavage of α4, altering its phosphatase regulatory function. Conclusion: Defects in this regulatory process may underlie the MAP hypophosphorylation and hyperphosphorylation seen in Opitz syndrome and Alzheimer disease. Significance: Pharmacological agents that interfere with α4 monoubiquitination or cleavage are potential therapeutics to treat Alzheimer disease.