Proteasomal Inhibition Redirects the PrP-Like Shadoo Protein to the Nucleus.

Abstract:

:The Shadoo protein (Sho) exhibits homology to the hydrophobic region of the cellular isoform of prion protein (PrPC). As prion-infected brains gradually accumulate infectivity-associated isoforms of prion protein (PrPSc), levels of mature endogenous Sho become reduced. To study the regulatory effect of the proteostatic network on Sho expression, we investigated the action of lactacystin, MG132, NH4Cl, and 3-methyladenine (3-MA) in two cell culture models. In primary mixed neuronal and glial cell cultures (MNGCs) from transgenic mice expressing wild-type Sho from the PrP gene promoter (Tg.Sprn mice), lactacystin- and MG132-mediated inhibition of proteasomal activity shifted the repertoire of Sho species towards unglycosylated forms appearing in the nuclei; conversely, the autophagic modulators NH4Cl and 3-MA did not affect Sho or PrPC glycosylation patterns. Mouse N2a neuroblastoma cells expressing Sho under control of a housekeeping gene promoter treated with MG132 or lactacystin also showed increased nuclear localization of unglycosylated Sho. As two proteasomal inhibitors tested in two cell paradigms caused redirection of Sho to nuclei at the expense of processing through the secretory pathway, our findings define a balanced shift in subcellular localization that thereby differs from the decreases in net Sho species seen in prion-infected brains. Our data are indicative of a physiological pathway to access Sho functions in the nucleus under conditions of impaired proteasomal activity. We also infer that these conditions would comprise a context wherein Sho's N-terminal nucleic acid-binding RGG repeat region is brought into play.

journal_name

Mol Neurobiol

journal_title

Molecular neurobiology

authors

Kang SG,Mays CE,Daude N,Yang J,Kar S,Westaway D

doi

10.1007/s12035-019-1623-1

subject

Has Abstract

pub_date

2019-11-01 00:00:00

pages

7888-7904

issue

11

eissn

0893-7648

issn

1559-1182

pii

10.1007/s12035-019-1623-1

journal_volume

56

pub_type

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