Optineurin, a multifunctional protein involved in glaucoma amyotrophic lateral sclerosis and antiviral signalling.
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2010-12
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Abstract
Glaucomas are a heterogeneous group of neurodegenerative eye diseases that cause blindness and are one
of the leading causes of blindness worldwide. Loss of vision in glaucoma occurs due to death of retinal
ganglion cells (RGCs) in the optic nerve head (Quigley 1999). Some of the genes known to be involved
in causing glaucoma in adults are myocilin, optineurin and WDR36 (Stone et al. 1997; Rezaie et al. 2002;
Monemi et al. 2005; Ray and Mookherjee 2009). Mutations in the coding region of the gene OPTN,
which codes for the protein optineurin, are associated with certain types of glaucoma. In the original
study, families affected with normal tension glaucoma (a sub-type of adult onset primary open angle
glaucoma) were analysed for mutations in optineurin (Rezaie et al. 2002). Subsequent studies have shown
that in sporadic cases of glaucoma mutations in optineurin are rare, accounting for only about 1% of the
cases. Almost all the glaucoma-associated mutations in OPTN are single copy alterations. Most of these
mutations are missense mutations. One of the glaucoma-associated mutants (E50K) causes death of retinal
ganglion cells in vitro as well as in transgenic mice providing support to the suggestion that mutations in
optineurin cause glaucoma (Chalasani et al. 2007; Chi et al. 2010).
A recent report described that certain mutations in optineurin are the cause of familial amyotrophic
lateral sclerosis (ALS) (Maruyama et al. 2010). Like some forms of glaucomas, ALS is an adult onset
progressive neurodegenerative disorder whose hallmark is the selective death of motor neurons of
primary motor cortex, brainstem, and spinal cord. Mutations in optineurin were found in familial as well
as sporadic cases of ALS. Three types of mutations were observed, two of these being homozygous.
One of these homozygous mutations was deletion of exon 5, observed in familial ALS, and the other
was Q398X nonsense mutation found in both familial as well sporadic cases. A heterozygous missense
mutation E478G was observed in familial ALS (Maruyama et al. 2010). What are the functional defects
caused by mutations in optineurin? To address this question we need to understand the function of normal
optineurin.
Optineurin interacts with several proteins which are involved in various functions (table 1, fi gure 1).
On the basis of interactions and other experiments various functions have been proposed for optineurin
such as regulation of exocytosis and vesicle traffi c from the Golgi to the plasma membrane, organization
of the Golgi stacks, regulation of signalling to transcription factor NF-κB, antiviral signalling,
metabotropic glutamate receptor signalling and regulation of gene expression (Hattula and Peranen 2000;
Anborgh et al. 2005; Weisschuh et al. 2007; Zhu et al. 2007; Chalasani et al. 2009; del Toro et al. 2009;
Mankouri et al. 2010). Optineurin is phosphorylated on serine and tyrosine residues and exists as homohexamers
(Ying et al. 2010). Several optineurin-interacting proteins such as Rab8, Huntingtin, myosin
VI and TBC1D17 are involved in regulating vesicular membrane traffi c in various cells. Knockdown of
optineurin affects structure of the Golgi and reduces transport from the Golgi to the plasma membrane
(Sahlender et al. 2005). However, there is no report of any disruption of this transport (from the
Golgi to the plasma membrane) or exocytosis by any disease-associated mutant although overexpression
of the E50K mutant and to a lesser extent of wild-type optineurin causes breakdown of the Golgi
(Park et al. 2006). Recently we and others have shown that knockdown of optineurin reduces endocytic
traffi cking of transferrin and its receptor (transferrin receptor, TfR) to the recycling endosomes
(Nagabhushana et al. 2010; Park et al. 2010). A glaucoma-causing mutant of optineurin (E50K) impairs traffi cking of TfR possibly due to altered interactions with Rab8 and transferrin receptor. This impaired
traffi cking results in accumulation of TfR in large vesicular structures formed by E50K leading to lower
level of TfR at the cell surface and hence reduced uptake of transferrin by the E50K expressing cells.
It was suggested that impaired traffi cking caused by the E50K mutant might be the cause of cell death
induced by this mutant in RGCs (Nagabhushana et al. 2010; Park et al. 2010). Transport of neurotrophins
in the axons is crucial for the survival of neuronal cells. Blockade of axonal transport has been reported
in glaucoma in humans and in experimental animal models (Pease et al. 2000). However, the molecules
whose defective traffi cking by E50K optineurin causes RGC death in glaucoma need to be identifi ed.
Is the defective traffi cking of neurotrophins, transferrin or their receptors (or some other associated
molecules) responsible for RGC death?
Another function of optineurin is regulation of signalling to the transcription factor NF-κB. NF-κB plays
a key role in the expression of many genes involved in regulating immune response, apoptosis, cell cycle
and its deregulation is involved in the pathogenesis of many diseases including some neurodegenerative
disorders. Upon treatment of cells with TNFα, trimerization of TNF receptor results in the assembly of a
signalling complex at the cytoplasmic side of the plasma membrane. In this complex RIP is ubiquitinated
(by the addition of Lys63-linked ubiquitin chains) which then recruits NF-κB essential modulator (NEMO),
the regulatory sub-unit of a kinase complex, IKK. This leads to activation of the catalytic subunits
of the IKK complex, IKKα and β, that phosphorylate inhibitor of κB (IκB) resulting in its degradation.
This enables nuclear translocation of NF-κB to activate transcription of target genes (Hayden and
Ghosh 2008). Knockdown of optineurin increases basal as well as TNFα-induced NF-κB activity
whereas overexpressed optineurin inhibits it. This negative regulation of NF-κB activity is believed
to be the result of competition of optineurin with NEMO for binding to polyubiquitinated RIP (Zhu et al.
2007). C-terminal half of optineurin shows considerable homology with NEMO. However the regulation
of NF-κB activity by optineurin is likely to be far more complex because optineurin interacts with two
other negative regulators of NF-κB- CYLD, a deubiquitinase and A20, a ubiquitin editing enzyme
(Chalasani et al. 2009). In human T-lymphotropic virus type 1 (HTLV-1) infected cells optineurin interacts
with TAX1BP1 and a viral protein TAX1 resulting in sustained activation of NF-κB and ubiquitination of
TAX1 (Journo et al. 2009). Thus role of optineurin in the regulation of NF-κB is cell type and stimulus
dependent.
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Keywords
ALS, glaucoma, NF-κB signalling, optineurin, vesicle traffi cking
Citation
Swarup Ghanshyam, Nagabhushana Ananthamurthy. Optineurin, a multifunctional protein involved in glaucoma amyotrophic lateral sclerosis and antiviral signalling. Journal of Biosciences. 2010 Dec; 35(4): 501-505.