Ubiquitin-activating enzyme activity contributes to differential accumulation of mutant huntingtin in brain and peripheral tissues.

Huntington's disease (HD) belongs to a family of neurodegenerative diseases caused by misfolded proteins and shares the pathological hallmark of selective accumulation of misfolded proteins in neuronal cells. Polyglutamine expansion in the HD protein, huntingtin (Htt), causes selective neurodegeneration that is more severe in the striatum and cortex than in other brain regions, but the mechanism behind this selectivity is unknown. Here we report that in HD knock-in mice, the expression levels of mutant Htt (mHtt) are higher in brain tissues than in peripheral tissues.

Differential ubiquitination and degradation of huntingtin fragments modulated by ubiquitin-protein ligase E3A.

Ubiquitination of misfolded proteins, a common feature of many neurodegenerative diseases, is mediated by different lysine (K) residues in ubiquitin and alters the levels of toxic proteins. In Huntington disease, polyglutamine expansion causes N-terminal huntingtin (Htt) to misfold, inducing neurodegeneration. Here we report that shorter N-terminal Htt fragments are more stable than longer fragments and find differential ubiquitination via K63 of ubiquitin.

Proteolytic and non-proteolytic roles of ubiquitin and the ubiquitin proteasome system in transcriptional regulation.

The ubiquitin proteasome system (UPS) regulates perhaps the most intriguing balance in all of biology: how cells control protein function and malfunction in order to regulate, and eventually eliminate, the old and error prone while simultaneously synthesizing and orchestrating the new. In light of the growing notion that ubiquitination and the 26S proteasome are central to a multiplicity of diverse cellular functions, we discuss here the proteolytic and non-proteolytic roles of the UPS in regulating pathways ultimately involved in protein synthesis and activity including roles in epigenetics, transcription, and post-translational modifications. This article is part of a Special Issue entitled The 26S Proteasome: When degradation is just not enough!

Phosphorylation and ubiquitination of degron proximal residues are essential for class II transactivator (CIITA) transactivation and major histocompatibility class II expression.

Major histocompatibility (MHC) class II molecules are cell surface glycoproteins that present extracellular antigens to CD4(+) T cells and are essential for initiation of the adaptive immune response. MHC class II expression requires recruitment of a master regulator, the class II transactivator (CIITA), to the MHC class II promoter. Post-translational modifications to CIITA play important roles in modulating CIITA mediated transcription of various genes in different cell types.

Association of the 19S proteasomal ATPases with the ATPase-binding domain of CIITA is essential for CIITA stability and MHC class II expression.

Major histocompatibility class II (MHC class II) molecules are glycoproteins that present extracellular antigens to CD4(+) T cells and are essential for initiation of adaptive immune responses. MHC class II expression requires recruitment of a master regulator, the class II transactivator (CIITA), to the MHC class II promoter. Others and we have earlier linked CIITA to the ubiquitin-proteasome system by showing that mono-ubiquitination of CIITA increases its transactivity, whereas poly-ubiquitination of CIITA leads to its degradation.

Regulation of acetylation at the major histocompatibility complex class II proximal promoter by the 19S proteasomal ATPase Sug1.

Recent studies have made evident the fact that the 19S regulatory component of the proteasome has functions that extend beyond degradation, particularly in the regulation of transcription. Although 19S ATPases facilitate chromatin remodeling and acetylation events in yeast (Saccharomyces cerevisiae), it is unclear if they play similar roles in mammalian cells. We have recently shown that the 19S ATPase Sug1 positively regulates the transcription of the critical inflammatory gene for major histocompatibility complex class II (MHC-II) by stabilizing enhanceosome assembly at the proximal promoter.

The 19S proteasome ATPase Sug1 plays a critical role in regulating MHC class II transcription.

Emerging evidence in yeast suggests roles for ATPases of the 19S proteasome as mediators of transcriptional systems through their association with actively transcribed promoters, facilitation of clearance of paused elongation complexes and recruitment of coactivators. Although 19S subunits also regulate mammalian transcription, their role in recruiting transcription factors remains unclear. Here, we demonstrate for the first time a role for the 19S proteasome ATPase Sug1 in regulating transcription of the critical adaptive immune gene, MHC class II.