The Ubiquitin Ligase Praja1 Reduces NRAGE Expression and Inhibits Neuronal Differentiation of PC12 Cells

Abstract

Evidence suggests that regulated ubiquitination of proteins plays a critical role in the development and plasticity of the central nervous system. We have previously identified the ubiquitin ligase Praja1 as a gene product induced during fear memory consolidation. However, the neuronal function of this enzyme still needs to be clarified. Here, we investigate its involvement in the nerve growth factor (NGF)-induced differentiation of rat pheochromocytoma (PC12) cells. Praja1 co-localizes with cytoskeleton components and the neurotrophin receptor interacting MAGE homologue (NRAGE). We observed an enhanced expression of Praja1 after 3 days of NGF treatment and a suppression of neurite formation upon Praja1 overexpression in stably transfected PC12 cell lines, which was associated with a proteasome-dependent reduction of NRAGE levels. Our data suggest that Praja1, through ubiquitination and degradation of NRAGE, inhibits neuronal differentiation. The two murine isoforms, Praja1.1 and Praja1.2, appear to be functionally homologous in this respect.

A Comprehensive Guide to the MAGE Family of Ubiquitin Ligases

“…Notably, Mage-d1-null mice display decreased extracellular serotonin levels and increased serotonin transporter (SERT) protein levels, suggesting that deficiency in MAGE-D1 induces both behavioral and neurological phenotypes of depression [81]. Further investigation revealed that MAGE-D1 regulates ubiquitination and proteasomal degradation of SERT, consistent with previous reports associating MAGE-D1 with PRAJA-1 E3 ligase and modulation of Msx2- and Dlx5-dependent transcription as well as neuronal differentiation [81–83]. In an alternative Mage-d1-deficient (hemizygous) mouse model, loss of Mage-d1 results in reduced social interactions, decreased sexual activity leading to infertility in males, reduced motor activity, late-onset obesity associated with hyperphagia, and increased anxiety-like behaviors [84].…”

PJA1 Coordinates with the SMC5/6 Complex To Restrict DNA Viruses and Episomal Genes in an Interferon-Independent Manner

“…1B and C ), suggesting that PJA1 acts as a potential antiviral factor against HBV. PJA1 encodes two isoforms, PJA1 and PJA1B, with a 55-amino-acid difference ( 6 ), and the N-terminus-lacking isoform, PJA1B, was reported to function consistently with full-length PJA1 in nerve growth factor-induced differentiation of rat pheochromocytoma cells ( 50 ). Here, we generated four plasmids expressing PJA1; PJA1B; PJA1ΔR, which lacks the RING domain; and PJA1BΔR, which lacks the RING domain ( Fig.…”

The melanoma-associated antigen 1 (MAGEA1) protein stimulates the E3 ubiquitin-ligase activity of TRIM31 within a TRIM31-MAGEA1-NSE4 complex

“…The latter interactions may represent different interaction types. For example, MAGED1-Praja1 interaction, which directs MAGED1 to proteasomedependent degradation, 31,48 represents a substrate-ligase type of interaction rather than the stimulation-of-ligase type of interaction proposed for MAGEA1-TRIM31. In other words, different MAGE-RING interactions may have different natures, may serve different purposes and may have different evolutionary origins.…”