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c20orf3

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Official Full Name
adipocyte plasma membrane associated protein
Synonyms
BSCv; C20orf3; APMAP; adipocyte plasma membrane associated protein; cb351; zgc:55833; zgc:85628; wu:fb50a03; adipocyte plasma membrane-associated protein; bscv (C20orf3) homolog

Adipocyte membrane associated protein (APMAP) is a novel integral membrane protein. The N-terminus (41 amino acids) of APMAP is located in the cytosol; it contains a transmembrane structure consisting of 20 amino acid residues in the middle; the C-terminus (356 amino acids) is located outside the cell, which is a combination part of APMAP and other signaling molecules. In addition, amino acid residues 159 to 162 of APMAP also constitute an N-glycosylation site. Kim et al found that the 196th asparagine residue in the N-glycosylation site of APMAP is human-specific, but the molecular function associated with this specific site is not yet clear. According to the APMAP once-transmembrane, the N-terminus of the peptide chain is intracellular and the C-terminal extracellular structure, it can be classified as a secondary membrane protein. In the human body, APMAP is widely expressed in various tissues and organs such as liver, placenta, central nervous system, blood vessels, kidneys and islets.

Figure 1. Molecular hypothesis for the regulation of APP-CTFs/Ab levels by APMAP. (Mosser, et al. 2014).

APMAP Function

APMAP plays an important role in adipocyte differentiation. Silencing APMAP expression in 3T3-L1 preadipocytes inhibited its differentiation. At the same time, it can downregulate the differentiation of adipocytes related markers, including peroxisome proliferators-activated receptors γ(PPARγ), CAAT/enhancer binding proteins α (C/EBPα). The expression of fatty acid binding protein 4 (FABP4) was down-regulated.In addition, APMAP localizes to the endoplasmic reticulum in preadipocytes and localizes to cell membranes in mature adipocytes. Overexpression of APMAP in preadipocytes results in accumulation only in the endoplasmic reticulum and does not induce differentiation of preadipocytes or accelerate their differentiation. Therefore, APMAP plays a role in promoting the differentiation of pre-adipocytes, which is premised on its transfer to the cell membrane.

The expression of APMAP is directly regulated by PPARγ. PPARγ is mainly expressed in adipose tissue and immune system. It is closely related to adipocyte differentiation, insulin resistance and immune system. It is a target molecule for the action of insulin sensitizer thiazolidinediones (TZDs). PPARγ binds to the downstream region of the APMAP transcription initiation site to induce APMAP expression, whereas APMAP expression is not detected in mouse embryonic fibroblasts (MEF) lacking PPARγ, and lipid synthesis and cell differentiation are also blocked. It indicated that PPARγ is the key to APMAP's role in regulating adipocyte differentiation. In addition, the PPARγ agonist rosiglitazone not only significantly induced APMAP expression in MEF, but also partially reversed the differentiation defect of MEF due to APMAP silencing.

APMAP has the same six-leaf β propeller fold structure as PON1 in paraoxonases (PONs). PONs are detoxification enzymes widely distributed in humans. They are composed of PON1 to PON3 and are mainly distributed in organs such as liver, kidney, and brain. Because APMAP is similar to PON1 structure, the structure of APMAP and PONs is compared. It is found that both APMAP and PONs contain a single transmembrane structure and the same exon at the N-terminus. In addition, APMAP has aryl esterase activity, PONs have lactonase activity, and both are widely expressed in organs involved in the detoxification process.

APMAP and Disease

Gestational diabetes mellitus (GDM) is a special type of diabetes whose main pathophysiological mechanism is insulin resistance. In order to study the specific mechanism of insulin resistance in patients with GDM, Ma et al. selected GDM patients and 6 patients with normal glucose tolerance and collected omental adipose tissue samples for non-labeled quantitative proteomics. It was found that APMAP is in the forefront of differentially expressed proteins and APMAP is down-regulated in the omental adipose tissue of GDM patients. Subsequently, RNA interference (RNAi) was used to inhibit the expression of APMAP in 3T3-L1 adipocytes, and it was found that the insulin signaling pathway was impaired and the NF-κB signal transduction pathway was activated. This study shows that down-regulation of APMAP expression in omental adipose tissue may be one of the important mechanisms of inflammation activation and insulin resistance in GDM patients.

The development of non-invasive, more accurate diagnostic techniques has been one of the research hotspots of primary Sjögren’s syndrome (pSS). In order to excavate new biomarkers from saliva and tears in patients with pSS, 27 patients with pSS and 32 healthy controls were enrolled in the study, taking saliva and tears. The results showed that the APMAP content in the saliva of patients with pSS increased significantly. In addition, Skarstein et al. biopsy of small salivary glands in patients with Sjögren's syndrome found that the incidence of adipose tissue replacement in this area increased, accompanied by an increase in IL-6 levels, indicating that adipose tissue in this region actively participated in the immune response. Upregulation of APMAP in saliva can serve as a marker of adipocyte involvement in disease progression. Detection of APMAP levels in saliva may be used as a new tool to aid in the diagnosis of pSS in the future.

The main pathological hallmark of Alzheimer's disease (AD) is the excessive accumulation of neurotoxic amyloid β (Aβ) in the brain. Mosser et al. found in cell experiments that inhibition of APMAP expression in HeLa cells and HEK cells reduced the stability of APP protein, leading to an increase in APP-CTFs and Aβ levels. The addition of chloroquine, an inhibitor of the lysosomal-autophagosome pathway, increased the APP-CTFs and Aβ more significantly. APP-CTFs and Aβ can be degraded by the lysosomal-autophagosome system. Therefore, Mosser et al believe that the down-regulation of APMAP expression can hinder the degradation of APP-CTFs and Aβ by the lysosome-autophagosome system, resulting in the accumulation of both in the cells. The above results show that APMAP can inhibit the expression of Aβ and is an endogenous inhibitor of Aβ.

References:

  1. Kim, D. S., & Hahn, Y. (2015). The acquisition of novel n-glycosylation sites in conserved proteins during human evolution. Bmc Bioinformatics, 16(1), 29.
  2. Ma, Y., Gao, J., Yin, J., Gu, L., Liu, X., & Chen, S., et al. (2016). Identification of a novel function of adipocyte plasma membrane-associated protein (apmap) in gestational diabetes mellitus by proteomic analysis of omental adipose tissue. Journal of Proteome Research, 15(2).
  3. Aqrawi, L. A., Galtung, H. K., Vestad, B., Øvstebø R, Thiede, B., & Rusthen, S., et al. (2017). Identification of potential saliva and tear biomarkers in primary sjögren’s syndrome, utilising the extraction of extracellular vesicles and proteomics analysis. Arthritis Research & Therapy, 19(1), 14.
  4. Skarstein, K., Aqrawi, L. A., ØIjordsbakken, G., Jonsson, R., & Jensen, J. L. (2016). Adipose tissue is prominent in salivary glands of sjögrenâs syndrome patients and appears to influence the microenvironment in these organs. Autoimmunity, 49(5), 1.
  5. Mosser, S., Alattia, J. R., Dimitrov, M., Matz, A., Pascual, J., & Schneider, B. L., et al. (2014). The adipocyte differentiation protein apmap is an endogenous suppressor of aβ production in the brain. Human Molecular Genetics, 24(2), 371-82.