Granulin

Last updated
GRN
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases GRN , CLN11, GEP, GP88, PCDGF, PEPI, PGranulin, granulin precursor
External IDs OMIM: 138945 MGI: 95832 HomoloGene: 1577 GeneCards: GRN
Orthologs
SpeciesHumanMouse
Entrez

2896

14824

Ensembl

ENSG00000030582

ENSMUSG00000034708

UniProt

P28799

P28798

RefSeq (mRNA)

NM_001012479
NM_002087

NM_008175

RefSeq (protein)

NP_002078

NP_032201

Location (UCSC) Chr 17: 44.35 – 44.35 Mb Chr 11: 102.32 – 102.33 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse
Granulin
PDB 1g26 EBI.jpg
the solution structure of a well-folded peptide based on the 31-residue amino-terminal subdomain of human granulin a
Identifiers
SymbolGranulin
Pfam PF00396
InterPro IPR000118
PROSITE PDOC00634
SCOP2 1pcn / SCOPe / SUPFAM
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary

Granulin is a protein that in humans is encoded by the GRN gene. [5] [6] [7] Each granulin protein is cleaved from the precursor progranulin, a 593 amino-acid-long and 68.5 kDa protein. [8] While the function of progranulin and granulin have yet to be determined, both forms of the protein have been implicated in development, inflammation, cell proliferation and protein homeostasis. The 2006 discovery of the GRN mutation in a population of patients with frontotemporal dementia has spurred much research in uncovering the function and involvement in disease of progranulin in the body. While there is a growing body of research on progranulin's role in the body, studies on specific granulin residues are still limited.

Contents

Progranulin

Progranulin is the precursor protein for granulin. Cleavage of progranulin produces a variety of active 6 kDa granulin peptides. These smaller cleavage products are named granulin A, granulin B, granulin C, etc. Epithelins 1 and 2 are synonymous with granulins A and B, respectively. Cleavage of progranulin into granulin occurs either in the extracellular matrix or the lysosome. Elastase, proteinase 3 and matrix metalloproteinase are proteases capable of cleaving progranulin into individual granulin peptides. [8] [9] Progranulin and granulin can be further differentiated by their hypothesized opposing roles in the cell. While progranulin is associated with anti-inflammation, cleaved granulin peptides have been implicated in pro-inflammatory behavior. A C. elegans study showed that granulin peptides may also participate in toxic activity. [9]

Expression

Progranulin is expressed in a wide variety of cell types both in the periphery and in the central nervous system. Progranulin expression is low in early development, but increases as cells mature. [10] Cell types expressing progranulin include neurons, microglia, astrocytes and endothelial cells. [11] Progranulin has been found to be highly expressed in microglia and up-regulated during injury [11] [10] Within the brain, progranulin mRNA is highly expressed in pyramidal, hippocampal and Purkinje cells cells. [8]

Structure

Each individual granulin domain peptide is 60 amino acids in length. Granulin peptides are cysteine rich and capable of forming 6 disulfide bonds per residue. [9] The disulfide bonds form a central rod-like core that shuttles each individual granulin peptide into a stacked β-sheet configuration. [11] [8] The structure of the granulin protein is similar to the structure of proteins from protein families that consist of hormones, growth factors, ion channel modulators and enzyme inhibitors. [11] Because of progranulin's structural similarities to these proteins, much research was done to interrogate progranulin's potential role as a growth factor. When progranulin is secreted into the extracellular matrix, it is often glycosylated at 4 confirmed and 1 tentative N-linked glycosylation sites. [11] [9] The n-terminus of progranulin is hypothesized to be involved in the secretion of progranulin via secretory vesicles. [11] Specifically, Progranulin may be involved in regulating exosome excretion. [12] The C-terminus of progranulin is hypothesized to be the primary binding partner of SORT1, a receptor of extracellular progranulin. [13] [11] The structural differences between each individual granulin peptide have yet to be characterized.

Interactive partners

In the extracellular matrix, progranulin binds to receptors on several cell types resulting in either activation of a signal transduction pathway or engulfment into the cell. Several studies have shown progranulin's involvement in the binding of SORT1 and the subsequent trafficking of bounded progranulin to the lysosome. [11] One recent study has shown that progranulin may actually mediate prosaposin trafficking to the lysosome via SORT1. [14] However, the absence of SORT1 does not prevent exogenous progranulin from promoting neurite outgrowth or enhancing cell survival of GRN knockout cells, suggesting that other receptors are involved in mediating extracellular progranulin function [15] For example, SORT1 -/- neuronal cells are still able to bind progranulin. [15] Other studies have suggested tumor necrosis factor and EPH receptor A2 as potential progranulin facilitators. [11] After binding to the receptor, progranulin may induce and modulate signaling pathways such as MAPK/ERK, PI3K/Akt, and FAK. [9] [15] Gene ontology enrichment analysis reveals an association between progranulin and notch receptor signaling. [9] Granulin has also been shown to interact with Cyclin T1 [16] and TRIB3. [17]

Function

Development

Although progranulin expression increases as cells mature, [10] they are still involved in the development of multiple cell types. Progranulin is hypothesized to be a neurotrophic factor involved in corticogenisis. Induced pluripotent stem cell lines (IPSC) harboring the GRN mutation show a decrease in cortical neuronal differentiation ability. [18] A recent mice study suggests that progranulin may be involved in regulating the early development of cerebellar tissue by selecting for individual climbing fibers as they intersect and form synapses with Purkinje cells. [19] In addition, several studies implicate progranulin in synaptic pruning, a microglial process that occurs during development of the neural network. [20] Cytokines, a neuronal marker for synapse elimination, is found to be upregulated in neurons with the GRN mutation. [20] Increased cytokine tagging results in an increase in microglial density and activity around synapses. [20] Progranulin may also be involved in sexual determination during embryonic development. [8]

Inflammation and wound healing

Progranulin levels are elevated when tissue is inflamed. After wounding, keratinocytes, macrophages and neutrophils increase production of progranulin. [8] Neutrophils are capable of secreting elastase into the extracellular matrix that is capable of cleaving progranulin into granulin peptides, that promote further promote inflammation. [8] SLPI, inhibitors of elastase, are also released by neutrophils and macrophages to modulate progranulin cleavage. [8] Addition of granulin B in cultured epithelial cells causes cells to secrete IL-8, a chemical that attracts monocytes and neutrophils, which further suggests the involvement of granulin peptides in promoting inflammation. [8] The addition of exogenous SLPI and progranulin is able to alleviate the enhanced inflammatory response of mice that are unable to inhibit the cleavage of progranulin. [8]

Cell proliferation

Progranulin is highly expressed in cells that are highly proliferative in nature. [8] Several studies implicate progranulin in tumorigenesis and neuronal outgrowth. Progranulin promotes mitogenesis in epithelial cultures. [8] When two epithelial lines were cultured in media with recombinant PGRN, proliferation was stimulated. [9] Knockout of both progranulin homologues in a zebrafish model reduces axonal outgrowth. [10] In primary cortical and motor neurons, progranulin regulates neuronal outgrowth and survival. [10] In primary motor neurons, progranulin has been shown to increase neurite outgrowth by regulating the glycogen synthase kinase-3 beta. [10] Progranulin may function as an autocrine growth factor in tumorigenesis. [15]

Lysosomal function

The discovery of a GRN mutation leading to lysosomal storage disorder led to many studies that explored progranulin's role in regulating protein homeostasis via the lysosomal pathway. Transcriptional gene network interference study suggests that progranulin is highly involved in lysosomal function and organization. [21] Imaging studies have shown co-localization of progranulin and lysosomal marker LAMP-1. [11] Progranulin expression is regulated by TFEB, a transcription factor that mediates proteins involved in lysosomal biosynthesis. [11] Progranulin may be involved in regulating protease activity. Proteases that could be regulated by progranulin include prosaposin, which is cleaved into saposin peptides in the lysosome, and cathepsin D, the primary protease involved in protein aggregate break down. [9] GRN mutation shares similar neuropathology and clinical phenotype with CHMP2B and VCP mutations, genes that are both involved in the trafficking and breakdown of proteins involved in lysosomal function. [8]

Clinical significance

Frontotemporal dementia

Heterozygous mutation of the GRN gene leading to progranulin haploinsufficiency causes frontotemporal dementia. [22] [23] [24] These mutations include frameshift, splice site, nonsense signal peptide, Kozak sequence disruptions and missense mutations, which result in either nonsense-mediated decay or the production of non-functional protein. [8] Patients with GRN caused FTD (GRN-FTD) exhibit asymmetric brain atrophy, although age of onset, disease progression and clinical symptoms vary, suggesting that other genetic or environmental factors may be involved in disease expression. [10] [8] Pathological indicators include cytosolic ubiquitin deposits enriched in hyperphosphorylated TAR DNA-binding protein 43 (TDP-43), autophagy-related protein aggregates, ubiquitin-binding protein p62, lentiform intranuclear inclusions, dystrophic neurites and inflammation. [15] [8] [9] Patients with the heterozygote mutation exhibit a reduction of 70-80% serum progranulin levels when compared to controls. [15] Reprogrammed stem cells restore GRN mRNA levels to 50%, further suggesting that some other genetic or environmental factor is involved in regulating FTD disease expression. [15] Mice exhibit reduced autophagic flux and autophagy-dependent clearance. [9] Human FTLD-GRN derived fibroblasts show decrease lysosomal protease activity and lymphoblasts containing neuronal ceroid lipofuscinosis-like storage material. [9] FTLD-GRN IPSC cortical Neurons have enlarged vesicles, lipofuscin accumulation and cathepsin D deficiency. [9]

Neuronal ceroid lipofuscinosis

Homozygous mutation of the GRN gene causes neuronal ceroid lipofuscinosis (NCL) characterized by an accumulation of autofluorescent lipofuscin, enlarged vacuoles, impairment in lysosomal activity, retinal & brain degeneration, exaggerated inflammatory responses, microgliosis, astrogliosis and behavioral dysfunction such as OCD-like and disinhibition-like behavior. [15] [9] Aged GRN double mutant mice have lipofuscin deposits and enlarge lysosomes, while one group found phosphorylated TDP-43. [9]

Other diseases

Progranulin may also be involved in cancer development, atherosclerosis and other metabolic disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS) and limbic predominant age-related TDP-43 encephalopathy (LATE). [25]

Progranulin can promote cyclin D1 expression in breast cancer lines and phosphorylation of proteins through extracellular regulated kinase signaling pathways. [8] Progranulin is highly expressed in ovarian, adrenal carcinomas and immortalized epithelial cells. [8] There is a correlation between progranulin concentration and cancer severity. [9] Granulin release by macrophages has been associated with fibrotic hepatic metastasis in pancreatic cancer. [26] The human liver fluke Opisthorchis viverrini contributes to the development of bile duct (liver) cancer by secreting a granulin-like growth hormone. [27]

Progranulin may also be involved in promoting the progression of atherosclerosis. [15] While progranulin may be anti-atherogenic, granulins may be pro-atherogenic. [15] Increased serum and plasma progranulin levels in patients with type 2 diabetes and visceral obesity implicating progranulin in metabolic diseases. [15]

A recent genome-wide association study (GWAS) has found that genetic variations in GRN are associated with late-onset sporadic Alzheimer’s disease (LOAD). These genetic variations change the degradation pathways of misfolded protein contributing misfolded β-amyloid accumulation and plaque formation. [28]

Related Research Articles

<span class="mw-page-title-main">Frontotemporal dementia</span> Types of dementia involving the frontal or temporal lobes

Frontotemporal dementia (FTD), or frontotemporal degeneration disease, or frontotemporal neurocognitive disorder, encompasses several types of dementia involving the progressive degeneration of frontal and temporal lobes. FTDs broadly present as behavioral or language disorders with gradual onsets. The three main subtypes or variant syndromes are a behavioral variant (bvFTD) previously known as Pick's disease, and two variants of primary progressive aphasia – semantic variant (svPPA), and nonfluent variant (nfvPPA). Two rare distinct subtypes of FTD are neuronal intermediate filament inclusion disease (NIFID), and basophilic inclusion body disease. Other related disorders include corticobasal syndrome and FTD with amyotrophic lateral sclerosis (ALS) FTD-ALS also called FTD-MND.

<span class="mw-page-title-main">Tau protein</span> Group of six protein isoforms produced from the MAPT gene

The tau proteins are a group of six highly soluble protein isoforms produced by alternative splicing from the gene MAPT. They have roles primarily in maintaining the stability of microtubules in axons and are abundant in the neurons of the central nervous system (CNS), where the cerebral cortex has the highest abundance. They are less common elsewhere but are also expressed at very low levels in CNS astrocytes and oligodendrocytes.

<span class="mw-page-title-main">Amyloid-beta precursor protein</span> Mammalian protein found in Homo sapiens

Amyloid-beta precursor protein (APP) is an integral membrane protein expressed in many tissues and concentrated in the synapses of neurons. It functions as a cell surface receptor and has been implicated as a regulator of synapse formation, neural plasticity, antimicrobial activity, and iron export. It is coded for by the gene APP and regulated by substrate presentation. APP is best known as the precursor molecule whose proteolysis generates amyloid beta (Aβ), a polypeptide containing 37 to 49 amino acid residues, whose amyloid fibrillar form is the primary component of amyloid plaques found in the brains of Alzheimer's disease patients.

<span class="mw-page-title-main">Frontotemporal lobar degeneration</span> Medical condition

Frontotemporal lobar degeneration (FTLD) is a pathological process that occurs in frontotemporal dementia. It is characterized by atrophy in the frontal lobe and temporal lobe of the brain, with sparing of the parietal and occipital lobes.

<span class="mw-page-title-main">Neurodegenerative disease</span> Central nervous system disease

A neurodegenerative disease is caused by the progressive loss of structure or function of neurons, in the process known as neurodegeneration. Such neuronal damage may ultimately involve cell death. Neurodegenerative diseases include amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, multiple system atrophy, and prion diseases. Neurodegeneration can be found in the brain at many different levels of neuronal circuitry, ranging from molecular to systemic. Because there is no known way to reverse the progressive degeneration of neurons, these diseases are considered to be incurable; however research has shown that the two major contributing factors to neurodegeneration are oxidative stress and inflammation. Biomedical research has revealed many similarities between these diseases at the subcellular level, including atypical protein assemblies and induced cell death. These similarities suggest that therapeutic advances against one neurodegenerative disease might ameliorate other diseases as well.

<span class="mw-page-title-main">MHC class II</span> Protein of the immune system

MHC Class II molecules are a class of major histocompatibility complex (MHC) molecules normally found only on professional antigen-presenting cells such as dendritic cells, mononuclear phagocytes, some endothelial cells, thymic epithelial cells, and B cells. These cells are important in initiating immune responses.

<span class="mw-page-title-main">TIA1</span> Mammalian protein found in Homo sapiens

TIA1 or Tia1 cytotoxic granule-associated rna binding protein is a 3'UTR mRNA binding protein that can bind the 5'TOP sequence of 5'TOP mRNAs. It is associated with programmed cell death (apoptosis) and regulates alternative splicing of the gene encoding the Fas receptor, an apoptosis-promoting protein. Under stress conditions, TIA1 localizes to cellular RNA-protein conglomerations called stress granules. It is encoded by the TIA1 gene.

<span class="mw-page-title-main">GLB1</span> Protein

Galactosidase, beta 1, also known as GLB1, is a protein which in humans is encoded by the GLB1 gene.

<span class="mw-page-title-main">Cathepsin D</span> Protein-coding gene in the species Homo sapiens

Cathepsin D is a protein that in humans is encoded by the CTSD gene. This gene encodes a lysosomal aspartyl protease composed of a protein dimer of disulfide-linked heavy and light chains, both produced from a single protein precursor. Cathepsin D is an aspartic endo-protease that is ubiquitously distributed in lysosomes. The main function of cathepsin D is to degrade proteins and activate precursors of bioactive proteins in pre-lysosomal compartments. This proteinase, which is a member of the peptidase A1 family, has a specificity similar to but narrower than that of pepsin A. Transcription of the CTSD gene is initiated from several sites, including one that is a start site for an estrogen-regulated transcript. Mutations in this gene are involved in the pathogenesis of several diseases, including breast cancer and possibly Alzheimer disease. Homozygous deletion of the CTSD gene leads to early lethality in the postnatal phase. Deficiency of CTSD gene has been reported an underlying cause of neuronal ceroid lipofuscinosis (NCL).

<span class="mw-page-title-main">TGFBI</span> Protein-coding gene in the species Homo sapiens

Transforming growth factor, beta-induced, 68kDa, also known as TGFBI, is a protein which in humans is encoded by the TGFBI gene, locus 5q31.

<span class="mw-page-title-main">Colony stimulating factor 1 receptor</span> Protein-coding gene in the species Homo sapiens

Colony stimulating factor 1 receptor (CSF1R), also known as macrophage colony-stimulating factor receptor (M-CSFR), and CD115, is a cell-surface protein encoded by the human CSF1R gene. CSF1R is a receptor that can be activated by two ligands: colony stimulating factor 1 (CSF-1) and interleukin-34 (IL-34). CSF1R is highly expressed in myeloid cells, and CSF1R signaling is necessary for the survival, proliferation, and differentiation of many myeloid cell types in vivo and in vitro. CSF1R signaling is involved in many diseases and is targeted in therapies for cancer, neurodegeneration, and inflammatory bone diseases.

<span class="mw-page-title-main">FGF9</span>

Glia-activating factor is a protein that in humans is encoded by the FGF9 gene.

<span class="mw-page-title-main">VPS35</span> Protein-coding gene in the species Homo sapiens

Vacuolar protein sorting ortholog 35 (VPS35) is a protein involved in autophagy and is implicated in neurodegenerative diseases, such as Parkinson's disease (PD) and Alzheimer's disease (AD). VPS35 is part of a complex called the retromer, which is responsible for transporting select cargo proteins between vesicular structures and the Golgi apparatus. Mutations in the VPS35 gene (VPS35) cause aberrant autophagy, where cargo proteins fail to be transported and dysfunctional or unnecessary proteins fail to be degraded. There are numerous pathways affected by altered VPS35 levels and activity, which have clinical significance in neurodegeneration. There is therapeutic relevance for VPS35, as interventions aimed at correcting VPS35 function are in speculation.

<span class="mw-page-title-main">CLN6</span>

Ceroid-lipofuscinosis neuronal protein 6 is a protein that in humans is encoded by the CLN6 gene.

<span class="mw-page-title-main">TMEM106B</span>

Transmembrane protein 106B is a protein that is encoded by the TMEM106B gene. It is found primarily within neurons and oligodendrocytes in the central nervous system with its subcellular location being in lysosomal membranes. TMEM106B helps facilitate important functions for maintaining a healthy lysosome, and therefore certain mutations and polymorphisms can lead to issues with proper lysosomal function. Lysosomes are in charge of clearing out mis-folded proteins and other debris, and thus, play an important role in neurodegenerative diseases that are driven by the accumulation of various mis-folded proteins and aggregates. Due to its impact on lysosomal function, TMEM106B has been investigated and found to be associated to multiple neurodegenerative diseases.

<span class="mw-page-title-main">Cyclin-dependent kinase 5</span> Protein-coding gene in the species Homo sapiens

Cyclin-dependent kinase 5 is a protein, and more specifically an enzyme, that is encoded by the Cdk5 gene. It was discovered 15 years ago, and it is saliently expressed in post-mitotic central nervous system neurons (CNS).

Proteostasis is the dynamic regulation of a balanced, functional proteome. The proteostasis network includes competing and integrated biological pathways within cells that control the biogenesis, folding, trafficking, and degradation of proteins present within and outside the cell. Loss of proteostasis is central to understanding the cause of diseases associated with excessive protein misfolding and degradation leading to loss-of-function phenotypes, as well as aggregation-associated degenerative disorders. Therapeutic restoration of proteostasis may treat or resolve these pathologies. Cellular proteostasis is key to ensuring successful development, healthy aging, resistance to environmental stresses, and to minimize homeostatic perturbations from pathogens such as viruses. Cellular mechanisms for maintaining proteostasis include regulated protein translation, chaperone assisted protein folding, and protein degradation pathways. Adjusting each of these mechanisms based on the need for specific proteins is essential to maintain all cellular functions relying on a correctly folded proteome.

<span class="mw-page-title-main">C9orf72</span> Protein-coding gene in the species Homo sapiens

C9orf72 is a protein which in humans is encoded by the gene C9orf72.

<span class="mw-page-title-main">PLD3</span> Protein-coding gene in the species Homo sapiens

Phospholipase D3, also known as PLD3, is a protein that in humans is encoded by the PLD3 gene. PLD3 belongs to the phospholipase D superfamily because it contains the two HKD motifs common to members of the phospholipase D family, however, it has no known catalytic function similar to PLD1 or PLD2. PLD3 serves as a ssDNA 5' exonuclease in antigen presenting cells. PLD3 is highly expressed in the brain in both humans and mice, and is mainly localized in the endoplasmic reticulum (ER) and the lysosome.

There are more than 25 genes known to be associated with amyotrophic lateral sclerosis (ALS) as of June 2018, which collectively account for about 70% of cases of familial ALS (fALS) and 10% of cases of sporadic ALS (sALS). About 5–10% of cases of ALS are directly inherited. Overall, first-degree relatives of an individual with ALS have a 1% risk of developing ALS. ALS has an oligogenic mode of inheritance, meaning that mutations in two or more genes are required to cause disease.

References

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  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000034708 - Ensembl, May 2017
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  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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  25. ↑ Jo M, Lee S, Jeon YM, Kim S, Kwon Y, Kim HJ (October 2020). "The role of TDP-43 propagation in neurodegenerative diseases: integrating insights from clinical and experimental studies". Experimental & Molecular Medicine. 52 (10): 1652–1662. doi:10.1038/s12276-020-00513-7. PMC   8080625 . PMID   33051572.
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  27. ↑ Smout MJ, Laha T, Mulvenna J, Sripa B, Suttiprapa S, Jones A, et al. (October 2009). "A granulin-like growth factor secreted by the carcinogenic liver fluke, Opisthorchis viverrini, promotes proliferation of host cells". PLOS Pathogens. 5 (10): e1000611. doi:10.1371/journal.ppat.1000611. PMC   2749447 . PMID   19816559.
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