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Updated: Jun 9, 2026

Comparative Strategies for Ubiquitination Detection in Mammalian Cell Lysates Using SMAD2/SMURF2 as a Model
Published on: April 17, 2026
Smad ubiquitination regulatory factor-2 in progressive supranuclear palsy
M Nakamura1, H Ito, Y Nakamura
1Department of Neurology, Kansai Medical University Department of Neurology, Kitano Hospital and Neurological Center, Osaka, Japan.
Aims:
Smad ubiquitination regulatory factor-2 (Smurf2) is an E3 ligase that belongs to the HECT domain ubiquitin ligase family. Smurf2 can interact with Smad proteins and promote their ubiquitin-dependent degradation, thereby controlling the cellular levels of these signalling mediators. Phosphorylated Smad2/3 (pSmad2/3) was recently identified in phosphorylated tau (phospho-tau) inclusions in patients with progressive supranuclear palsy (PSP). As Smurf2 is the E3 ligase of pSmad2, we aimed at investigating the relationship among Smurf2, pSmad2/3 and phospho-tau in this study.
Methods:
The brains of six PSP and three control patients without neurological disorder were investigated by immunohistochemical analysis.
Results:
In the control subjects, Smurf2 immunoreactivity was not demonstrable in the neurones and glial cells, and that for pSmad2/3 was observed exclusively in neuronal and glial nuclei. In PSP patients, the pathognomonic neuronal and glial phospho-tau inclusions were immunopositive for both Smurf2 and pSmad2/3. The intensity of pSmad2/3 immunosignals of neuronal and glial nuclei containing phospho-tau inclusions was less than that for the cells without the inclusions. Triple immunofluorescence staining for Smurf2, pSmad2/3 and phospho-tau revealed co-localization of these proteins within the neuronal and glial inclusions; and in some globose neurofibrillary tangles, the Smurf2 immunoreactivity appeared more centrally distributed than that of pSmad2/3 and phospho-tau.
Conclusions:
This is the first demonstration of the presence of Smurf2 immunoreactivity in the phospho-tau inclusions in PSP. These findings suggest that Smurf2 plays a significant role in the pathomechanism of PSP by causing abnormal redistribution of neuronal nuclear pSmad2/3 to the cytoplasm.
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