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Can Zhang

An Emerging Role for Ubiquilin 1 in Regulating Protein Quality Control System and in Disease Pathogenesis

Abstract: The process of refolding or degrading misfolded proteins is the most important function of protein quality control (PQC) system. An imbalance between the capacity of PQC system and the quantity and severity of misfolded proteins may result in protein aggregate accumulation, which can ultimately contribute to a class of diseases referred to as conformational disorders. Numerous lines of evidence suggest that Ubiquilin 1 is an important component in PQC. Ubiquilin 1 has been indicated to be involved in the pathophysiology of neurodegenerative diseases and cancer. Here we review the evidence that Ubiquilin 1 is an important component of the PQC system and also review the role of Ubiquilin 1 in human diseases.


Proper cellular physiology relies on proteins attaining their biologically active, three dimensional structures. Some proteins spontaneously fold into these structures while other proteins require “chaperones” to assist them in achieving this physiological structure. These folding processes are efficient but not perfect and protein misfolding does occur. Misfolded proteins expose hydrophobic amino acids that are normally buried within the core of the protein structure. Because of this exposure and other physiochemical properties, misfolded proteins are prone to aggregation which can result in cell death and ultimately lead to a variety of disease states.

A protein quality control (PQC) system exists within eukaryotic cells to facilitate the efficient degradation of misfolded proteins. Currently, the primary PQC activities are believed to be found in the endoplasmic reticulum (ER), ubiquitin-proteasome system (UPS), and lysosome (Gardner et al., 2005; Goldberg, 2003; Martinez-Vicente and Cuervo, 2007). Misfolded proteins can first be recognized immediately after translation in the ER, where heat shock proteins (HSPs) bind misfolded proteins and catalyze refolding. If refolding is unsuccessful, misfolded proteins are then transported into the cytosol where they are targeted for degradation by the ubiquitin-proteasome system or by the lysosome.

The quantity and severity of misfolded proteins can overwhelm the capacity of the PQC system and may lead to protein aggregate accumulation. Misfolded proteins that can not be degraded tend to be more toxic to cells. Aggregated proteins can accumulate into an intracellular inclusion body termed aggresome which is considered a temporary protective mechanism to confine potentially toxic proteins. Dividing cells can relieve this toxicity by passing aggregated proteins onto daughter cells; however, in post-mitotic cells such as neurons this mechanism is not possible and may make these cells more susceptible to toxic protein aggregates. Therefore, disorders of protein folding and degradation are emerging as a fundamental mechanism in the pathogenesis of many diseases, especially neurodegenerative diseases.

There is a growing body of evidence that implicates Ubiquilin 1 as an important part of the PQC system and that Ubiquilin 1 may be involved in pathogenesis of neurodegeneration and cancer. Here we review the evidence that supports the role of Ubiquilin 1 in the PQC system and disease.

ER, UPS, and autophagy-lysosome system

The ER is the most important eukaryotic organelle for protein folding and degradation. Within the ER misfolded proteins are recognized by the unfolded protein response (UPR) which targets them for degradation by the ERAD or ERQD (ER-associated quality control and degradation) mechanisms. Once recognized, these misfolded proteins are degraded either by the UPS or the lysosome.

The UPS system is essential for many cellular processes, including the cell cycle, the regulation of gene expression, and responses to oxidative stress. In the UPS, misfolded proteins are first covalently labeled with ubiquitin, a small, evolutionarily conserved protein, through the process of ubiquitination or ubiquitinylation. This is an ATP-dependent process that involves the action of at least three enzymes that work in concert: a ubiquitin-activating enzyme (E1), a ubiquitin-conjugating enzyme (E2), and a ubiquitin ligase (E3) (Goldberg, 2003; Rubinsztein, 2006). Ubiquitinylation is an important regulatory tool that controls the concentration of key signaling proteins, such as those involved in cell cycle control, as well as removing misfolded, damaged, or mutant proteins that could be harmful to the cell. Abnormal ubiquitinylation of proteins can result in intracellular accumulations, i.e., aggresomes. Examples of such inclusions bodies include neurofibrillary tangles (Alzheimer’s disease), Lewy bodies (Parkinson’s disease), Pick bodies (Pick’s disease), and Mallory’s Hyalin (alcoholic liver disease). After a polyubiquitinated chain is formed, the proteins will be delivered to the proteasome specifically for degradation (Figure 1).

macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA).

Figure 1. Protein quality control systems in mammalian cells. Most proteins are degraded through ubiquitin-proteasome system (UPS) or lysosome system, the two essential components of protein quality control (PQC). Proteins are delivered to lysosomes from the extracellular media (heterophagy) or from inside the cell (autophagy). Mammalian cells carry out three different types of autophagy: macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA).

Larger misfolded proteins or organelles are degraded in the lysosome through hydrolytic reactions in its acidic environment. The degradation of intracellular components is called autophagy, while degradation of material originating from outside of the cell is called heterophagy (Figure 1). In general, lysosomal degradation is less specific than UPS mediated degradation. However, during a process called chaperone mediated autophagy (CMA), chaperones (particularly heat-shock proteins) selectively bind and transport substrate proteins with the sequence of KFERQ to a lysosomal receptor (LAMP-2A) which results in being endocytosed into the lysosome. Disorders of autophagy can result in intracellular protein aggregates and lead to several neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and polyglutamine diseases (Martinez-Vicente and Cuervo, 2007). 

Ubiquilin genes and proteins

The human genome encodes four structurally related Ubiquilin genes: Ubqln1, Ubqln2, Ubqln3, and Ubqln4. Ubqln1 is located on chromosome 9q22 and encodes two major isoforms containing either 589 amino acids or 561 amino acids. Ubqln2 is located on chromosome Xp11 and encodes the 624 amino acid Ubiquilin 2 protein. Ubqln3 is located on chromosome 11p15 and encodes the 655 amino acid Ubiquilin 3 protein. Finally, Ubqln4 is located on chromosome 1q21 and encodes the 601 amino acid Ubiquilin 4 protein. All the Ubiquilin family members are subcellularly localized to the cytosol but have different tissue expression patterns. Ubiquilin 1 is expressed ubiquitously. Ubiquilin 2 and 4 are expressed in brain, spleen, spleen, heart, liver, pancreas, and other tissues. Ubiquilin 3 is expressed exclusively in the testis. Ubiquilin proteins are structurally conserved protein and contain an ubiquitin-like domain in its N-terminus and an ubiquitin-associated domain in its C-terminus. Functionally Ubiquilin 1 binds numerous cytosolic or transmembrane proteins via the aforementioned functional domains and modulates their steady state levels. The functional form of Ubiquilin 1 is not clear since it is capable of forming homodimers. The monomer form has been shown to be functional.

Ubiquilin 1 and PQC system

A large amount of evidence shows that Ubiquilin 1 functions as an adaptor protein that links the ubiquitination machinery to the proteasome to affect protein degradation. Studies utilizing yeast have shown that the yeast homolog of Ubiquilin 1, Dsk2p, can form a trimeric complex with other two proteins, Rad23p and Cdc48, and deliver ubiquitinated proteins to the proteasome. This complex prevents misfolded protein aggregates from developing in the cytoplasm. In addition, Ubiquilin 1 mediates degradation of proteins involved in various biological processes, e.g., the protein-disulfide isomerase (in stress response), the nicotinic acetylcholine receptors (in neurotransmission), and the presenilin 1 (in neurodevelopment and neurodegeneration). It appears that Ubiquilin 1 can also enhance the polyubiquitination of NS5B, a crucial protein involved in hepatitis C virus (HCV) RNA transcription. If levels of misfolded proteins exceed the degradation capacity of proteasome, Ubiquilin 1 can promote aggresome formation. Examples include ataxin 3 (a deubiquitinating enzyme), HSJ1a (a co-chaperone), and EPS15 (epidermal growth factor substrate 15, an endocytic protein).

Ubiquilin 1 also regulates autophagy activity by binding to mTOR. A protein kinase, mTOR functions to control cell cycle progression and cell growth through regulation of translation. Inhibiting mTOR has been suggested to activate autophagy functions and increase the clearance of aggregated proteins in polyglutamine mutant model cells. It is not currently known how the Ubiquilin 1 and mTOR interaction affects mTOR activities.

Ubiquilin 1, PQC, and their involvement in diseases

Alzheimer’s disease (AD) is a genetically complex and heterogeneous disorder. Recent systematic meta-analysis results suggest that AD risk is modulated by numerous genes, each displaying a small yet significant effect on risk (Bertram et al., 2007). Approximately 70% of the genetic variance of AD has yet to be determined. Considerable genetic, biochemical, and molecular-biological evidence suggests that the excessive accumulation of a small peptide, Aβ, is the primary pathological event leading to AD (Tanzi and Bertram, 2005). Aβ is produced through a sequential cleavage pathway of β-amyloid precursor protein (APP). Proteins that alter APP cleavage activities have been considered good AD therapeutic targets.

Four genes have been confirmed to be involved in AD, which are APP, PSEN1, PSEN2, and ApoE (Tanzi and Bertram, 2005). Several lines of experimental evidence support a role for Ubiquilin 1, and by extension PQC, in AD pathogenesis. First, at the genetic level, Bertram et al. reported that a Ubiquilin 1 polymorphism substantially increased AD risk, possibly by influencing Ubiquilin 1 alternative splicing in the brain (Bertram et al., 2005). Second, at the neuropathological level, anti-Ubiquilin antibodies robustly stained neurofibrillary tangles and Lewy bodies in AD- and PD-affected brains, respectively. Third, functionally, Ubiquilin 1 regulates γ-secretase (the APP cleavage proteases which can produce Aβ) activity by regulating endoproteolysis of the presenilin 1 protein within the γ-secretase complex (Mah et al., 2000; Zhang et al., 2007). In addition, a functional interaction between Ubiquilin 1 and presenilin 1 was detected in vitro as well as in brain tissue of healthy controls and AD patients. Massey et al. reported Ubiquilin 1 and presenilin proteins co-localized in vesicular-like structure or ER- like pattern (Mah et al., 2000; Massey et al., 2005). Finally, Ubiquilin 1 affects APP trafficking and processing, thereby influencing the generation of Aβ. Taken together, these results strongly suggest that Ubiquilin 1 may be involved in AD pathogenesis.

Polyglutamine (PolyQ) diseases are a category of neurodegenerative diseases characterized by expanded PolyQ tracts. Based on clinical features, PolyQ diseases are classified into nine different types, e.g., Huntington’s disease and spinocerebellar ataxia type 1 (SCA1). Despite the variety of clinical symptoms, they seem to share the same underlying mechanism, namely, CAG trinucleotide repeat expansion within gene coding regions which results in abnormally large glutamine repeats. This expansion leads to aggregation of the affected protein which overwhelms the PQC system. Recent evidence suggested that Ubiquilin family proteins are involved in the pathophysiology of PolyQ diseases. Spinocerebellar ataxia type 1 is a genetic disorder clinically characterized by slowly progressive incoordination of gait and often associated with poor coordination of hands, speech, and eye movements. Mutations in the gene encoding ataxin 1 (ATX1 or SCA1) cause the disease. The interaction between Ataxin 1 and Ubiquilin 4 (also known as ataxin-1-interacting protein, A1UP) may be involved with spinocerebellar ataxia type 1 pathogenesis. Huntington’s disease is another genetic disorder characterized by mutations in the Huntingtin (Htt) gene. Mutant Huntingtin proteins (mHtt) form nuclear inclusions and neuropil aggregates (aggregates in neuronal processes) which result in neuronal cell death in select areas of the brain and are responsible for the abnormal body movements and lack of coordination observed in the disease. Wang and colleagues reported that Ubiquilin 1 suppresses polyQ-induced protein aggregation and toxicity in cells and in an animal model of Huntington’s disease (Wang et al., 2006).

Cancer is characterized by uncontrolled cell division. Cyclins and cyclin-dependent kinases (CDKs) are the two critical classes of molecules in regulation of cell cycle progression. Funakoshi and colleagues reported that Xenopus orthologue of Ubiquilin 1, XDRP1, binds cyclin A (A1 and A2) and arrests embryonic Xenopus cell division. Ubiquilin 1 has also been reported to interact with the tumor-suppressor proteins, e.g., DAN and S(1-5) protein, which modulate DNA synthesis and therefore cell division. Finally, in lung adenocarcinoma samples, Ubiquilin 1 mRNA and protein levels are both significantly increased. Interestingly, the phosphorylated form of the Ubiquilin 1 protein is significantly reduced in these same samples. Taken together, there is strong evidence that Ubiquilin 1 is involved in pathogenesis of a number of diseases.


In summary, the protein quality control (PQC) system is a complex intracellular system which refolds and degrades misfolded proteins. The main activities of PQC reside in the ER, UPS, and lysosome. First stages of PQC occur in the ER where refolding of misfolded proteins occurs through heat shock proteins and other chaperone proteins. UPS and lysosome seem to be the second stage of quality control. The proteins which can not be repaired in the ER undergo UPS- or lysosome-mediated degradation. To maintain normal cellular functions, these three systems need to coordinate their functions. Ubiquilin 1 is a key adaptor protein that has been implicated in ER and UPS for protein degradation. Data also suggests that Ubiquilin 1 might alter autophagy activities of the lysosome. Imbalance of the PQC system can lead to misfolded protein aggregation, cellular dysfunction or death, and ultimately to disease. PQC disruption is an emerging mechanism for many disorders, including Alzheimer’s disease, spinocerebellar ataxia type 1, Huntington’s disease, and cancer. Identifying agents that specifically modulate protein quality control system or Ubiquilin 1 activities may reveal novel avenues for therapeutic intervention.


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[Discovery Medicine, 8(40):18-22, 2009]

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