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FLASH GENE

Symbol

OPTN

contributors: mct/npt/pgu - updated : 24-10-2015

HGNC name	optineurin
HGNC id	17142

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Corresponding disease	ALS12 amyotrophic lateral sclerosis 12 GLC1E glaucoma, primary open angle 1E
Location	10p13      Physical location : 13.142.081 - 13.180.276
Synonym name	Huntingtin interacting protein L
	tumor necrosis factor alpha-inducible cellular protein containing leucine zipper domains
	nemo-related protein
	transcrption factor IIIA-interacting protein
	glaucoma 1, open angle, E (adult-onset)
	E3-14.7K-interacting protein
Synonym symbol(s)	FIP2, NRP, HYPL, TFIIIA-INTP, HIP7, ALS12, GLC1E

DNA

TYPE	functioning gene
STRUCTURE	38.20 kb     16 Exon(s)

10 Kb 5' upstream gene genomic sequence study

regulatory sequence	Promoter
	Binding site   transcription factor
text structure	three non-coding exons in the 5'-untranslated region and thirteen coding exons
	TNF activates optineurin promoter through NFKB-binding site in the core promoter
	a functional IRF1-binding site in the first intron of human optineurin gene that mediates IFNG-induced activation of the promoter

MAPPING

cloned

Y

linked

N

status

provisional

RNA

TRANSCRIPTS	type	messenger

text	three different variants resulting form alternative splicing at the 5'-UTR, but all have the same reading frame

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_001008211 16 - 3597 NP_001008212 36 577 - 2008 18385781 OPTN variant 1 NM_021980 14 - 3376 NP_068815 36 577 - 2008 18385781 OPTN variant 2 NM_001008212 15 - 3528 NP_001008213 36 577 three to four times less abundant than the variant 1 in trabecular meshwork and nonpigmented ciliary epithelium 2008 18385781 OPTN variant 3 NM_001008213 16 - 3582 NP_001008214 - 577 - 2008 18385781 OPTN variant 4

EXPRESSION

Type	ubiquitous

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Cardiovascular heart       highly Digestive intestine small intestine     highly Endocrine pancreas       highly Nervous nerve       highly Reproductive male system testis     highly Urinary kidney         Visual eye retina       Homo sapiens

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Connective adipose     highly Muscular striatum cardiac     Muscular striatum skeletal   highly Nervous central

cells

System Cell Pubmed Species Stage Rna symbol   digestive Lymphoid/Immune lymphocyte Visual cone photoreceptor Homo sapiens

cell lineage

cell lines

fluid/secretion

at STAGE

physiological period

fetal

Text	trabecular meshwork

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	leucine zipper motif
	one zinc finger motif, C2H2 type
	TBK1 binding site located between AAs 1-127 (N-terminal)
	tail region (423-577 AAs) of OPTN was necessary for binding with NRL

HOMOLOGY

interspecies

ortholog to murine Optn

Homologene

FAMILY

CATEGORY

adaptor , regulatory

SUBCELLULAR LOCALIZATION	plasma membrane
	intracellular
	intracellular,cytoplasm,organelle,membrane
	intracellular,cytoplasm,organelle,Golgi
	intracellular,cytoplasm,organelle,endosome
	intracellular,cytoplasm,cytosolic,vesicle
	intracellular,nucleus,nucleoplasm
text	myosin VI and OPTN colocalize with secretory vesicles at the plasma membrane

basic FUNCTION	blocks the protective effect of E3-14.7K on tumor necrosis factor-alpha-mediated cell killing (inhibiting cytolysis)
	critical adaptor that regulates the assembly of TAX1BP1 and post-translationally modified forms of Tax1, leading to sustained NF-kappaB activation
	involved in the pathogenesis of amyotrophic lateral sclerosis
	role for myosin VI and optineurin in regulation of fusion pores formed between secretory vesicles and the plasma membrane during the final stages of secretion
	involved in basic cellular functions including protein trafficking, maintenance of the Golgi apparatus, as well as NFKB pathway, antiviral, and antibacteria signaling
	important role in the spatial and temporal coordination of PLK1 activity
	OPTN suppresses nuclear factor-kappa B (NFKB) activity
	adaptor protein involved in signal transduction, membrane vesicle trafficking and autophagy
	polyubiquitin-binding protein that has been implicated in regulating cell signaling via its NFKB essential modulator-homologous C-terminal ubiquitin (Ub)-binding region
	is involved in several functions including regulation of endocytic trafficking, autophagy and signal transduction
	multifunctional protein involved in cellular morphogenesis, vesicle trafficking, maintenance of the Golgi complex, and transcription activation
	plays a central role in the adult-onset neuronal intranuclear inclusion disease pathogenesis, and may be a major component of neuronal intranuclear inclusions

CELLULAR PROCESS

PHYSIOLOGICAL PROCESS

nervous system

text	playing a putative neuroprotective role in the eye and optic nerve

PATHWAY

metabolism

signaling

signal transduction , sensory transduction/vision

implicated in tumor necrosis factor alpha signaling pathway

a component

HACE1-OPTN axis synergistically suppresses growth and tumorigenicity of lung cancer cells

INTERACTION

DNA

RNA

small molecule	metal binding,
	Zn2+

protein	Huntingtin (HD)
	Ras-associated protein RAB8
	transcription factor IIIA
	adenovirus E3-14.7K
	binds to the C-terminal region of TBK1 and deletion of the C-terminal 40 residues of TBK1, which prevents interaction with TANK, also abolishes interaction with OPTN
	interacts cooperatively with TAX1BP1 (OPTN and TAX1BP1 cooperate to modulate Tax1 ubiquitination and NF-kappaB activation)
	is associated with a myosin phosphatase complex (MP), which antagonizes the mitotic function of PLK1
	mediates the interaction and colocalisation of TBC1D17 with RAB8A
	IRF1 mediates IFNG-induced optineurin promoter activation
	RAB25 associates with OPTN and can recruit this effector protein to endosomal membranes
	endogenous optineurin is dispensable for NFKB activation but necessary for optimal IRF3 activation in immune cells
	HACE1 ubiquitylates OPTN and promotes its interaction with p62/SQSTM1 to form the autophagy receptor complex, thus accelerating autophagic flux
	APP interacts with MAP1LC3B via OPTN/optineurin and is degraded by an autophagic process mediated by the PRKAA1 pathway
	constitutive interaction of TBK1 with OPTN and the ability of OPTN to bind to ubiquitin chains are essential for TBK1 recruitment and kinase activation on mitochondria
	OPTN is a positive regulator TBK1 via a bipartite interaction between these molecules

cell & other

REGULATION

activated by

IRF1, that cooperates with NFKB to activate optineurin promoter

induced by	TNF-alpha, interferon
		its expression is induced by cytokines

Phosphorylated by

TBK1 that directly phosphorylated the autophagic adaptor optineurin (OPTN)

ASSOCIATED DISORDERS

corresponding disease(s)

GLC1E , ALS12

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function constitutional     --other   in Huntington disease optineurin is present in intranuclear, neuropil and perikaryal inclusions

Susceptibility

to glaucoma with normal tension to Paget disease

Variant & Polymorphism other	variant M98K modifying initial intraocular pression in patients with primary open angle glaucoma
	rs1561570 strongly associated with Paget disease

Candidate gene

Marker

Therapy target

ANIMAL & CELL MODELS