Involvement of ubiquilin-1 transcript variants in protein degradation and accumulation

Abstract

Controlled management of protein levels and quality is essential for normal cellular function. Specific molecular chaperones and foldases monitor the levels and assist correct folding of proteins. The ubiquitin-proteasome system recognizes and degrades misfolded proteins that can otherwise be harmful to cells. However, when misfolded or aggregated proteins excessively accumulate, they may be sequestered to the microtubule-organizing center to form aggresomes. These may then be removed from cells by autophagocytosis. Abnormal protein accumulation and aggregation is a common hallmark of many neurodegenerative diseases. In a recent study, we provide evidence that specific transcript variants (TVs) of ubiquilin-1, which are genetically and functionally associated to Alzheimer’s disease (AD), regulate proteasomal and aggresomal targeting of presenilin-1 (PS1), a key player in AD pathogenesis. Our study together with current data provide interesting implications for ubiquilin-1 and its TVs in the pathogenesis of AD and other neurodegenerative diseases involving abnormal protein aggregation. 

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Acknowledgments

This study was supported by EC FP6, MEST-CT-2005-019217 (to J.V.), the Health Research Council of the Academy of Finland (to A.H., H.S. and M.H.), EVO grant 5772708 of Kuopio University Hospital (to H.S.), the Nordic Centre of Excellence in Neurodegeneration (to H.S. and M.H.), Sigrid Juselius Foundation (to M.H.) and the strategic funding of the University of Eastern Finland.

Figures and Tables

Figure 1 Ubiquilin-1 transcript variants (TV). TV1, the full-length form of ubiquilin-1 consists of 11 exons. The N-terminus of ubiquilin-1 protein harbors a UBL (ubiquitin-like) domain (shaded in red), which mediates interaction with the proteasome. The C-terminal UBA (ubiquitin-associated) domain binds poly-ubiquitinated proteins (shaded in green). TV2 lacks exon 8 (turquoise). TV3 lacks exons 2, 3 and 4 and thus the majority of the UBL domain. TV4 contains the first 3 exons. The frame shift leading to a 32-amino acid insertion after the exon 3/5 junction creates a unique short C-terminus (dark blue) and thus results in the lack of the UBA domain.

Figure 2 Schematic representation of the suggested function of ubiquilin-1 TV1 and TV3 in proteasomal and aggresomal targeting of PS1. TV1 binds poly-ubiquitinated PS1 via its UBA domain and shuttles PS1 to the 26S proteasome for degradation. UBL domain mediates the interaction between TV1 and the UIM (ubiquitin-interacting motif) domain of the proteasome 19S cap subunit S5a. Under excessive PS1 accumulation, TV1 may also target PS1 to the aggresomes (dashed arrow). TV3, which lacks majority of the UBL domain, is impeded in binding to the proteasome and predominantly targets accumulated PS1 to the aggresomes. Ub; ubiquitin.

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