UniProt functional annotation for Q96LT7



	UniProt functional annotation for Q96LT7

UniProt code: Q96LT7.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

Function: Component of the C9orf72-SMCR8 complex, a complex that has guanine nucleotide exchange factor (GEF) activity and regulates autophagy (PubMed:27193190, PubMed:27103069, PubMed:27617292, PubMed:28195531). In the complex, C9orf72 and SMCR8 probably constitute the catalytic subunits that promote the exchange of GDP to GTP, converting inactive GDP-bound RAB8A and RAB39B into their active GTP- bound form, thereby promoting autophagosome maturation (PubMed:27103069). The C9orf72-SMCR8 complex also acts as a regulator of autophagy initiation by interacting with the ATG1/ULK1 kinase complex and modulating its protein kinase activity (PubMed:27617292). Positively regulates initiation of autophagy by regulating the RAB1A- dependent trafficking of the ATG1/ULK1 kinase complex to the phagophore which leads to autophagosome formation (PubMed:27334615). Acts as a regulator of mTORC1 signaling by promoting phosphorylation of mTORC1 substrates (PubMed:27559131). Plays a role in endosomal trafficking (PubMed:24549040). May be involved in regulating the maturation of phagosomes to lysosomes (By similarity). Regulates actin dynamics in motor neurons by inhibiting the GTP-binding activity of ARF6, leading to ARF6 inactivation (PubMed:27723745). This reduces the activity of the LIMK1 and LIMK2 kinases which are responsible for phosphorylation and inactivation of cofilin, leading to cofilin activation (PubMed:27723745). Positively regulates axon extension and axon growth cone size in spinal motor neurons (PubMed:27723745). Plays a role within the hematopoietic system in restricting inflammation and the development of autoimmunity (By similarity). {ECO:0000250|UniProtKB:Q6DFW0, ECO:0000269|PubMed:24549040, ECO:0000269|PubMed:27103069, ECO:0000269|PubMed:27193190, ECO:0000269|PubMed:27334615, ECO:0000269|PubMed:27559131, ECO:0000269|PubMed:27617292, ECO:0000269|PubMed:27723745, ECO:0000269|PubMed:28195531}.

Function: [Isoform 1]: Regulates stress granule assembly in response to cellular stress. {ECO:0000269|PubMed:27037575}.

Function: [Isoform 2]: Does not play a role in regulation of stress granule assembly in response to cellular stress. {ECO:0000269|PubMed:27037575}.

Subunit: Interacts with SMCR8; the interaction is direct (PubMed:27559131, PubMed:27617292). Component of the C9orf72-SMCR8 complex, at least composed of C9orf72, SMCR8 and WDR41 (PubMed:27193190, PubMed:27103069, PubMed:27559131, PubMed:27617292, PubMed:28195531). The C9orf72-SMCR8 complex associates with the ATG1/ULK1 kinase complex (PubMed:27617292, PubMed:28195531). Interacts with ATG1/ULK1 kinase complex members ULK1, ATG13 and RB1CC1 (PubMed:27334615). Interacts with HNRNPA1, HNRNPA2B1 and UBQLN2 (PubMed:24549040). Interacts with small Rab GTPase RAB1A; the interaction mediates recruitment of RAB1A to the ATG1/ULK1 kinase complex (PubMed:27334615). Also interacts with small Rab GTPase RAB7A (By similarity). Interacts with cofilin (PubMed:27723745). Interacts with GTP-binding proteins ARF1 and ARF6 (By similarity). {ECO:0000250|UniProtKB:Q6DFW0, ECO:0000269|PubMed:24549040, ECO:0000269|PubMed:27103069, ECO:0000269|PubMed:27193190, ECO:0000269|PubMed:27334615, ECO:0000269|PubMed:27559131, ECO:0000269|PubMed:27617292, ECO:0000269|PubMed:27723745, ECO:0000269|PubMed:28195531}.

Subcellular location: Nucleus {ECO:0000269|PubMed:21944779, ECO:0000269|PubMed:27037575}. Cytoplasm {ECO:0000269|PubMed:21944778, ECO:0000269|PubMed:27037575, ECO:0000269|PubMed:27193190}. Cytoplasm, P-body {ECO:0000269|PubMed:27037575}. Cytoplasm, Stress granule {ECO:0000269|PubMed:27037575}. Endosome {ECO:0000269|PubMed:24549040}. Lysosome {ECO:0000269|PubMed:24549040, ECO:0000269|PubMed:27559131}. Cytoplasmic vesicle, autophagosome {ECO:0000269|PubMed:24549040}. Secreted {ECO:0000269|PubMed:24549040}. Cell projection, axon {ECO:0000269|PubMed:27723745}. Cell projection, growth cone {ECO:0000269|PubMed:27723745}. Perikaryon {ECO:0000250|UniProtKB:Q6DFW0}. Note=Detected in the cytoplasm of neurons from brain tissue (PubMed:21944778). Detected in the nucleus in fibroblasts (PubMed:21944779). During corticogenesis, transitions from being predominantly cytoplasmic to a more even nucleocytoplasmic distribution (By similarity). {ECO:0000250|UniProtKB:Q6DFW0, ECO:0000269|PubMed:21944778, ECO:0000269|PubMed:21944779, ECO:0000269|PubMed:27037575}.

Subcellular location: [Isoform 1]: Perikaryon {ECO:0000269|PubMed:26174152}. Cell projection, dendrite {ECO:0000269|PubMed:26174152}. Note=Expressed diffusely throughout the cytoplasm and dendritic processes of cerebellar Purkinje cells. Also expressed diffusely throughout the cytoplasm of spinal motor neurons. {ECO:0000269|PubMed:26174152}.

Subcellular location: [Isoform 2]: Nucleus membrane {ECO:0000269|PubMed:26174152}; Peripheral membrane protein {ECO:0000305}. Nucleus {ECO:0000269|PubMed:26174152}. Note=Detected at the nuclear membrane of cerebellar Purkinje cells and spinal motor neurons. Also shows diffuse nuclear expression in spinal motor neurons. {ECO:0000269|PubMed:26174152}.

Tissue specificity: Both isoforms are widely expressed, including kidney, lung, liver, heart, testis and several brain regions, such as cerebellum. Also expressed in the frontal cortex and in lymphoblasts (at protein level). {ECO:0000269|PubMed:21944778, ECO:0000269|PubMed:21944779}.

Disease: Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 (FTDALS1) [MIM:105550]: An autosomal dominant neurodegenerative disorder characterized by adult onset of frontotemporal dementia and/or amyotrophic lateral sclerosis in an affected individual. There is high intrafamilial variation. Frontotemporal dementia is characterized by frontal and temporal lobe atrophy associated with neuronal loss, gliosis, and dementia. Patients exhibit progressive changes in social, behavioral, and/or language function. Amyotrophic lateral sclerosis is characterized by the death of motor neurons in the brain, brainstem, and spinal cord, resulting in fatal paralysis. {ECO:0000269|PubMed:21944778, ECO:0000269|PubMed:21944779, ECO:0000269|PubMed:22936364}. Note=The disease is caused by variants affecting the gene represented in this entry. In the first intron of the gene, the expansion of a GGGGCC hexanucleotide that can vary from 10 to thousands of repeats, represents the most common genetic cause of both familial and sporadic FTDALS. The hexanucleotide repeat expansion (HRE) is structurally polymorphic and during transcription, is responsible for the formation of RNA and DNA G-quadruplexes resulting in the production of aborted transcripts at the expense of functional transcripts. The accumulation of those aborted transcripts may cause nucleolar stress and indirectly cell death (PubMed:24598541). The expanded GGGGCC repeats are bidirectionally transcribed into repetitive RNA, which forms sense and antisense RNA foci. Remarkably, despite being within a non-coding region, these repetitive RNAs can be translated in every reading frame to form five different dipeptide repeat proteins (DPRs) -- poly-GA, poly-GP, poly-GR, poly-PA and poly- PR -- via a non-canonical mechanism known as repeat-associated non-ATG (RAN) translation. These dipeptide repeat proteins (DPRs) co-aggregate in the characteristic SQSTM1-positive TARDBP negative inclusions found in FTLD/ALS patients with C9orf72 repeat expansion (PubMed:24132570). {ECO:0000269|PubMed:24132570, ECO:0000269|PubMed:24598541}.

Miscellaneous: [Isoform 1]: Encoded by 2 transcripts differing in the 5' non-coding region.

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



Function:		Component of the C9orf72-SMCR8 complex, a complex that has guanine nucleotide exchange factor (GEF) activity and regulates autophagy (PubMed:27193190, PubMed:27103069, PubMed:27617292, PubMed:28195531). In the complex, C9orf72 and SMCR8 probably constitute the catalytic subunits that promote the exchange of GDP to GTP, converting inactive GDP-bound RAB8A and RAB39B into their active GTP- bound form, thereby promoting autophagosome maturation (PubMed:27103069). The C9orf72-SMCR8 complex also acts as a regulator of autophagy initiation by interacting with the ATG1/ULK1 kinase complex and modulating its protein kinase activity (PubMed:27617292). Positively regulates initiation of autophagy by regulating the RAB1A- dependent trafficking of the ATG1/ULK1 kinase complex to the phagophore which leads to autophagosome formation (PubMed:27334615). Acts as a regulator of mTORC1 signaling by promoting phosphorylation of mTORC1 substrates (PubMed:27559131). Plays a role in endosomal trafficking (PubMed:24549040). May be involved in regulating the maturation of phagosomes to lysosomes (By similarity). Regulates actin dynamics in motor neurons by inhibiting the GTP-binding activity of ARF6, leading to ARF6 inactivation (PubMed:27723745). This reduces the activity of the LIMK1 and LIMK2 kinases which are responsible for phosphorylation and inactivation of cofilin, leading to cofilin activation (PubMed:27723745). Positively regulates axon extension and axon growth cone size in spinal motor neurons (PubMed:27723745). Plays a role within the hematopoietic system in restricting inflammation and the development of autoimmunity (By similarity). {ECO:0000250\|UniProtKB:Q6DFW0, ECO:0000269\|PubMed:24549040, ECO:0000269\|PubMed:27103069, ECO:0000269\|PubMed:27193190, ECO:0000269\|PubMed:27334615, ECO:0000269\|PubMed:27559131, ECO:0000269\|PubMed:27617292, ECO:0000269\|PubMed:27723745, ECO:0000269\|PubMed:28195531}.



Function:		[Isoform 1]: Regulates stress granule assembly in response to cellular stress. {ECO:0000269\|PubMed:27037575}.



Function:		[Isoform 2]: Does not play a role in regulation of stress granule assembly in response to cellular stress. {ECO:0000269\|PubMed:27037575}.


Subunit:		Interacts with SMCR8; the interaction is direct (PubMed:27559131, PubMed:27617292). Component of the C9orf72-SMCR8 complex, at least composed of C9orf72, SMCR8 and WDR41 (PubMed:27193190, PubMed:27103069, PubMed:27559131, PubMed:27617292, PubMed:28195531). The C9orf72-SMCR8 complex associates with the ATG1/ULK1 kinase complex (PubMed:27617292, PubMed:28195531). Interacts with ATG1/ULK1 kinase complex members ULK1, ATG13 and RB1CC1 (PubMed:27334615). Interacts with HNRNPA1, HNRNPA2B1 and UBQLN2 (PubMed:24549040). Interacts with small Rab GTPase RAB1A; the interaction mediates recruitment of RAB1A to the ATG1/ULK1 kinase complex (PubMed:27334615). Also interacts with small Rab GTPase RAB7A (By similarity). Interacts with cofilin (PubMed:27723745). Interacts with GTP-binding proteins ARF1 and ARF6 (By similarity). {ECO:0000250\|UniProtKB:Q6DFW0, ECO:0000269\|PubMed:24549040, ECO:0000269\|PubMed:27103069, ECO:0000269\|PubMed:27193190, ECO:0000269\|PubMed:27334615, ECO:0000269\|PubMed:27559131, ECO:0000269\|PubMed:27617292, ECO:0000269\|PubMed:27723745, ECO:0000269\|PubMed:28195531}.
Subcellular location:		Nucleus {ECO:0000269\|PubMed:21944779, ECO:0000269\|PubMed:27037575}. Cytoplasm {ECO:0000269\|PubMed:21944778, ECO:0000269\|PubMed:27037575, ECO:0000269\|PubMed:27193190}. Cytoplasm, P-body {ECO:0000269\|PubMed:27037575}. Cytoplasm, Stress granule {ECO:0000269\|PubMed:27037575}. Endosome {ECO:0000269\|PubMed:24549040}. Lysosome {ECO:0000269\|PubMed:24549040, ECO:0000269\|PubMed:27559131}. Cytoplasmic vesicle, autophagosome {ECO:0000269\|PubMed:24549040}. Secreted {ECO:0000269\|PubMed:24549040}. Cell projection, axon {ECO:0000269\|PubMed:27723745}. Cell projection, growth cone {ECO:0000269\|PubMed:27723745}. Perikaryon {ECO:0000250\|UniProtKB:Q6DFW0}. Note=Detected in the cytoplasm of neurons from brain tissue (PubMed:21944778). Detected in the nucleus in fibroblasts (PubMed:21944779). During corticogenesis, transitions from being predominantly cytoplasmic to a more even nucleocytoplasmic distribution (By similarity). {ECO:0000250\|UniProtKB:Q6DFW0, ECO:0000269\|PubMed:21944778, ECO:0000269\|PubMed:21944779, ECO:0000269\|PubMed:27037575}.
Subcellular location:		[Isoform 1]: Perikaryon {ECO:0000269\|PubMed:26174152}. Cell projection, dendrite {ECO:0000269\|PubMed:26174152}. Note=Expressed diffusely throughout the cytoplasm and dendritic processes of cerebellar Purkinje cells. Also expressed diffusely throughout the cytoplasm of spinal motor neurons. {ECO:0000269\|PubMed:26174152}.
Subcellular location:		[Isoform 2]: Nucleus membrane {ECO:0000269\|PubMed:26174152}; Peripheral membrane protein {ECO:0000305}. Nucleus {ECO:0000269\|PubMed:26174152}. Note=Detected at the nuclear membrane of cerebellar Purkinje cells and spinal motor neurons. Also shows diffuse nuclear expression in spinal motor neurons. {ECO:0000269\|PubMed:26174152}.
Tissue specificity:		Both isoforms are widely expressed, including kidney, lung, liver, heart, testis and several brain regions, such as cerebellum. Also expressed in the frontal cortex and in lymphoblasts (at protein level). {ECO:0000269\|PubMed:21944778, ECO:0000269\|PubMed:21944779}.
Disease:		Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 (FTDALS1) [MIM:105550]: An autosomal dominant neurodegenerative disorder characterized by adult onset of frontotemporal dementia and/or amyotrophic lateral sclerosis in an affected individual. There is high intrafamilial variation. Frontotemporal dementia is characterized by frontal and temporal lobe atrophy associated with neuronal loss, gliosis, and dementia. Patients exhibit progressive changes in social, behavioral, and/or language function. Amyotrophic lateral sclerosis is characterized by the death of motor neurons in the brain, brainstem, and spinal cord, resulting in fatal paralysis. {ECO:0000269\|PubMed:21944778, ECO:0000269\|PubMed:21944779, ECO:0000269\|PubMed:22936364}. Note=The disease is caused by variants affecting the gene represented in this entry. In the first intron of the gene, the expansion of a GGGGCC hexanucleotide that can vary from 10 to thousands of repeats, represents the most common genetic cause of both familial and sporadic FTDALS. The hexanucleotide repeat expansion (HRE) is structurally polymorphic and during transcription, is responsible for the formation of RNA and DNA G-quadruplexes resulting in the production of aborted transcripts at the expense of functional transcripts. The accumulation of those aborted transcripts may cause nucleolar stress and indirectly cell death (PubMed:24598541). The expanded GGGGCC repeats are bidirectionally transcribed into repetitive RNA, which forms sense and antisense RNA foci. Remarkably, despite being within a non-coding region, these repetitive RNAs can be translated in every reading frame to form five different dipeptide repeat proteins (DPRs) -- poly-GA, poly-GP, poly-GR, poly-PA and poly- PR -- via a non-canonical mechanism known as repeat-associated non-ATG (RAN) translation. These dipeptide repeat proteins (DPRs) co-aggregate in the characteristic SQSTM1-positive TARDBP negative inclusions found in FTLD/ALS patients with C9orf72 repeat expansion (PubMed:24132570). {ECO:0000269\|PubMed:24132570, ECO:0000269\|PubMed:24598541}.
Miscellaneous:		[Isoform 1]: Encoded by 2 transcripts differing in the 5' non-coding region.