NCL proteomics Flashcards
Smpd1
The SMPD1 gene provides instructions for making the enzyme acid sphingomyelinase (ASM), which is responsible for breaking down a fatty substance called sphingomyelin into another lipid called ceramide
Gba
GBA stands for glucocerebrosidase. GBA breaks down glucocerebroside, a large molecule in the cell membrane, into glucose and ceramide. When cells die, GBA breaks down glucocerebroside so the components can be reused to form new cells.
Asah1
The ASAH1 gene encodes the enzyme acid ceramidase, which breaks down ceramides into sphingosine and fatty acids in lysosomes. Ceramides are involved in many cell functions, including cell growth, differentiation, and apoptosis. Acid ceramidase helps recycle ceramides to create new ones. Acid ceramidase also has a “reverse” enzymatic activity that can synthesize ceramide from sphingosine and fatty acids. The pH at which this synthesis reaction occurs is different from the pH at which the hydrolysis reaction occurs, suggesting that acid ceramidase may have different functions depending on its subcellular location and the local pH.
Asah2
The Asah2 gene encodes neutral ceramidase, an enzyme that breaks down ceramide, a second messenger in many cellular events, to produce sphingosine.
ceramides
Ceramide, the precursor of all complex sphingolipids, is a potent signaling molecule that mediates key events of cellular pathophysiology. In the nervous system, the sphingolipid metabolism has an important impact. Neurons are polarized cells and their normal functions, such as neuronal connectivity and synaptic transmission, rely on selective trafficking of molecules across plasma membrane. Sphingolipids are abundant on neural cellular membranes and represent potent regulators of brain homeostasis. Ceramide intracellular levels are fine-tuned and alteration of the sphingolipid–ceramide profile contributes to the development of age-related, neurological and neuroinflammatory diseases. The purpose of this review is to guide the reader towards a better understanding of the sphingolipid–ceramide pathway system. First, ceramide biology is presented including structure, physical properties and metabolism. Second, we describe the function of ceramide as a lipid second messenger in cell physiology. Finally, we highlight the relevance of sphingolipids and ceramide in the progression of different neurodegenerative diseases.
Gpld1
Glycosylphosphatidylinositol‐specific phospholipase D1 (GPLD1) hydrolyzes inositol phosphate linkages in proteins anchored to the cell membrane. Mice overexpressing GPLD1 show enhanced neurogenesis and cognition.
Glycosylphosphatidylinositol-specific phospholipase D (GPLD1) is an enzyme that performs several biological functions, including:
Hydrolyzing GPI-anchored proteins
GPLD1 cleaves the inositol phosphate linkages in proteins that are anchored to the cell membrane. This releases the anchored proteins into the extracellular environment.
Regulating chronic diseases
GPLD1 is involved in the pathogenesis of many chronic diseases, including metabolic diseases, cancer, and neurological disorders.
Improving cognitive impairment
Exercise can increase GPLD1 expression, which can help with cognitive impairment and glucose metabolism in type 2 diabetes. GPLD1 levels can also be increased without exercise to improve cognitive impairment.
Releasing mucous barrier
GPLD1 releases a protective mucous barrier from the oral mucosa.
GPLD1 is primarily secreted by the liver and is abundant in serum.
Ppt1
Palmitoyl-protein thioesterase 1 (PPT1) is an enzyme that removes fatty acids from proteins in lysosomes, which are compartments within cells that break down molecules:
Protein breakdown: PPT1 removes long-chain fatty acids, like palmitate, from proteins, which helps break them down when they are no longer needed.
Developmental biology: PPT1 is required for the development of neurons and the function of synapses, which are the connections between nerve cells.
Autophagy: PPT1 depalmitoylates proteins in lysosomes before they are degraded.
Muscle differentiation: PPT1 plays a critical role in the differentiation of skeletal myoblasts.
Tumor growth: PPT1 promotes tumor growth and is a molecular target of chloroquine derivatives in cancer.
Ppt2
The palmitoyl protein thioesterase-2 (PPT2) protein is a lysosomal enzyme that removes thioester-linked fatty acyl groups from various substrates:
Cell metabolism: PPT2 is involved in cell metabolism by cutting the thioester linkage between a fatty acid and cysteine in lipid-modified proteins.
Lysosomal thioester catabolism: PPT2 targets lysosomes through the mannose 6-phosphate receptor pathway and has strong activity against palmitoylated model substrates.
Fatty acid chain length specificity: PPT2 hydrolyzes very-long chain fatty acids more efficiently than PPT1.
Pld4
Phospholipase D4 (PLD4) is a transmembrane glycoprotein that has multiple functions, including:
Regulating kidney fibrosis: PLD4 is upregulated in mouse models of kidney fibrosis and in biopsy samples from patients with tubulointerstitial fibrosis. Targeting PLD4 could be a novel therapeutic strategy to reverse kidney fibrosis.
Digesting single-stranded DNA: PLD4 is a 5’->3’ DNA exonuclease that digests single-stranded DNA (ssDNA).
Regulating inflammatory cytokine responses: PLD4 regulates inflammatory cytokine responses by degrading nucleic acids.
Involved in phagocytosis: PLD4 is involved in the phagocytosis of microglia in the central nervous system (CNS).
Influencing myelination: PLD4-deficient mice have a mild but significant delay in myelination in the cerebellum and corpus callosum.
Synthesizing S,S-BMP: PLD4 synthesizes S,S-BMP, a key phospholipid enabling lipid degradation in lysosomes.
Vdac1
Voltage-dependent anion channel 1 (VDAC1) is a protein that regulates the flow of ions, metabolites, and other substances across the outer mitochondrial membrane:
Mitochondrial function
VDAC1 is a key regulator of mitochondrial function, including metabolism, energy sources, and apoptosis.
Cell life and death
VDAC1 plays a role in cell life and death by regulating the release of apoptotic proteins from the mitochondria.
Mitochondrial gatekeeper
VDAC1 acts as a mitochondrial gatekeeper, interacting with over 100 proteins and orchestrating the interaction between mitochondrial and cellular activities.
Inflammation
VDAC1 can regulate mitochondrial function by interacting with organelles that have Ca2+ channels. Ca2+ plays an important role in the inflammatory response, so VDAC1 may be a potential target for treating inflammation.
Cancer
VDAC1 is highly expressed in tumors, and silencing VDAC1 expression can inhibit the growth of cancer cells and tumors.
VDAC1 is involved in a number of processes, including: Maintaining retinal morphology, Regulating autophagy, and Participating in endoplasmic reticulum (ER)-mitochondria cross-talk.
Pitpnc1
This gene encodes a member of the phosphatidylinositol transfer protein family. The encoded cytoplasmic protein plays a role in multiple processes including cell signaling and lipid metabolism by facilitating the transfer of phosphatidylinositol between membrane compartments. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene, and a pseudogene of this gene is located on the long arm of chromosome 1.
[Isoform 1]: Catalyzes the transfer of phosphatidylinositol (PI) and phosphatidic acid (PA) between membranes (PubMed:10531358, 22822086). Binds PA derived from the phospholipase D signaling pathway and among the cellular PA species, preferably binds to the C16:0/16:1 and C16:1/18:1 PA species (PubMed:22822086). ( PITC1_HUMAN,Q9UKF7 )
[Isoform 2]: Catalyzes the transfer of phosphatidylinositol between membranes. ( PITC1_HUMAN,Q9UKF7 )
Ubap2l
Ubiquitin-associated protein 2-like (UBAP2L) is a protein that performs many functions, including:
Stress granule assembly
UBAP2L is a key protein in the assembly of stress granules (SGs), which are non-membranous structures that help cells survive under stress. UBAP2L associates with other proteins, such as G3BP1, Caprin1, FXR1/2, and FMRP, to form SGs.
Nuclear pore complex homeostasis
UBAP2L helps maintain the homeostasis of nuclear pore complexes at the nuclear envelope.
RNA polymerase II ubiquitylation
UBAP2L is involved in the ubiquitylation and degradation of RNA polymerase II (RNAPII) after UV irradiation.
Oncogenic role
UBAP2L plays a role in the growth and metastasis of cancer cells, particularly in gastric, breast, and hepatocellular carcinoma (HCC). UBAP2L may regulate the PI3K/Akt and P53 signaling pathways, which are commonly dysregulated in cancerous cells.
Processing body (PB) formation
UBAP2L contributes to the formation of PBs, and can nucleate hybrid granules that contain both SG and PB components.
Ttyh2/Ttyh3
TTYHs have been reported to form Ca2+- and cell volume-regulated anion channels structurally distinct from any characterized protein family with potential roles in cell adhesion, migration, and developmental signaling. In the presence of Ca2+, TTYH2 and TTYH3 form homomeric cis-dimers bridged by extracellularly coordinated Ca2+. Strikingly, in the absence of Ca2+, TTYH2 forms trans-dimers that span opposing membranes across a ~130 Å intermembrane space as well as a monomeric state. All TTYH structures lack ion conducting pathways and we do not observe TTYH2-dependent channel activity in cells. We conclude TTYHs are not pore forming subunits of anion channels and their function may involve Ca2+-dependent changes in quaternary structure, interactions with hydrophobic molecules near the extracellular membrane surface, and/or association with additional protein partners.
Ppap2b
PPAP2B, also known as Lipid Phosphate Phosphatase 3 (LPP3), is a protein that performs a number of functions, including:
Maintaining vascular integrity
PPAP2B helps maintain the integrity of the endothelial monolayer, which is the lining of blood vessels.
Promoting anti-inflammatory phenotype
PPAP2B helps promote an anti-inflammatory phenotype in response to atherorelevant flows.
Inhibiting LPA receptor-mediated signaling
PPAP2B suppresses signaling mediated by LPA receptors, which are associated with the activation of blood and vascular cells, as well as epithelial cell proliferation and migration.
Converting phosphatidic acid to diacylglycerol
PPAP2B catalyzes the conversion of phosphatidic acid (PA) to diacylglycerol (DG).
Hydrolyzing lysophosphatidic acid
PPAP2B actively hydrolyzes extracellular lysophosphatidic acid (LPA).
Associated with Wnt signaling
PPAP2B is associated with Wnt signaling, which is important for the proper formation of tissues like the heart, bone, and muscle during embryonic development.
CLN3/5:
Wdfy1
WDFY1 (WD Repeat And FYVE Domain Containing 1) is a protein that plays a role in several processes, including:
Immune response: WDFY1 is an adaptor protein that strengthens the interaction between TLR3 and TLR4, and the adaptor TRIF. This interaction is important for the innate immune response, and for the production of inflammatory cytokines and type I interferons.
Endocytic trafficking: WDFY1 is involved in endocytic trafficking and autophagy. Overexpression of WDFY1 can lead to defective endocytic trafficking and autophagy.
Hematopoietic stem cells: WDFY1 may play a role in maintaining hematopoietic stem cells.
Schizophrenia: WDFY1 protein levels are upregulated in the brain of patients with schizophrenia.
Ciliogenesis: WDFY1 is essential for normal ciliogenesis.
Endosomal membrane protein WDFY1 interacts with both Toll‐like receptors and recruits the adaptor TRIF, enabling downstream signaling. WDFY1 potentiates IRF3 and NF‐kB activation, as well as type I IFN and inflammatory cytokine production in response to poly(I:C) and LPS.
Class switch recombination (CSR)
Class switch recombination (CSR) is a DNA process that changes the type of antibody a B cell produces:
Explanation
CSR allows B cells to switch from producing one type of antibody, like IgM, to producing another, like IgG, IgE, or IgA. The new antibody is better able to protect against the pathogen.
Process
CSR involves the activation of enzymes that create DNA double-strand breaks in the Ig heavy chain locus. These breaks lead to the recombination of the variable heavy-chain (VDJ) segment with a different constant heavy (CH) chain gene.
Regulation
B cells use a complex regulatory framework to ensure that the DNA breaks are repaired productively, and not in a way that could lead to lymphoma.
Significance
CSR is important to understand because dysregulation can lead to self-reactive BCRs and B cell lymphomas. Patients with class-switch recombination deficiency (CSR-D) often have recurrent bacterial infections.
Igh-3
The 3′ regulatory region (3′RR) of the immunoglobulin heavy chain (IgH) cluster controls a number of functions, including:
Class switch recombination (CSR): The 3′RR modulates CSR by enhancing the transcription of C(H) genes. However, the 3′RR is not essential for CSR, and deleting it in a mouse B cell line only slightly reduces CSR.
IgH expression: The 3′RR is required for high levels of IgH expression in plasma cells.
B cell maturation: The 3′RR plays a role in B cell maturation in mammals.
Autoimmune diseases: The 3′RR1 hs1.2 enhancer is associated with autoimmune diseases.
The 3′RR is located downstream of the C(H) locus and is about 28 kb long. The 3′RR’s effects are largely mediated by activating specific epigenetic marks in the DNA it targets. This suggests that targeting the 3′RR could be a potential strategy for treating mature B-cell lymphomas.
