CHMP2A

What is CHMP2A protein?

CHMP2A gene (charged multivesicular body protein 2A) is a protein coding gene which situated on the long arm of chromosome 19 at locus 19q13. CHMP2A belongs to the chromatin-modifying protein/charged multivesicular body protein (CHMP) family. These proteins are components of ESCRT-III (endosomal sorting complex required for transport III), a complex involved in degradation of surface receptor proteins and formation of endocytic multivesicular bodies (MVBs). The CHMP2A protein is consisted of 222 amino acids and CHMP2A molecular weight is approximately 25.1 kDa.

What is the function of CHMP2A protein?

CHMP2A protein is a key intracellular protein responsible for regulating the transport of substances between the endoplasmic reticulum and the Golgi apparatus, and is a part of the ESCRT-III complex. It is involved in the process of cytoplasmic division at the end of cell division and the formation of autophagosomes during autophagy. Abnormal function of CHMP2A has been associated with a variety of diseases, including certain neurodegenerative diseases and cancer. In cancer, CHMP2A may be involved in regulating the proliferation and migration of tumor cells. Therefore, CHMP2A not only plays an important role in cell biological processes, but may also be a potential target for future treatment of related diseases.

CHMP2A related signaling pathway

The CHMP2A protein is part of essential transport III (ESCRT-III) of the endosomal sorting complex, which is involved in the formation of polyvesicles and the biogenesis of extracellular vesicles (EVs). In addition, CHMP2A-deficient tumor cells increased NK cell migration by secreting more CXCL10 and CXCL12. At the same time, since tumor-derived EVs can inhibit NK cell activity via MICA/B and TRAIL, the absence of CHMP2A limits tumor cell secretion of EVs, thereby enhancing NK cell-mediated cytotoxicity. These studies suggest that inhibition or inactivation of CHMP2A activity may increase NK cell-mediated antitumor activity, providing a potential new strategy for cancer treatment.

CHMP2A related diseases

The CHMP2A protein plays a role in a variety of diseases, especially in tumor immune escape. CHMP2A, a component of the ESCRT-III complex, influences the sensitivity of tumor cells to natural killer (NK) cell-mediated cytotoxicity by regulating extracellular vesicles (EVs) secretion. In the head and neck squamous cell carcinoma (HNSCC) model, the loss of CHMP2A resulted in tumor cells being more prone to be killed by NK cells and increased infiltration of NK cells and other immune cells in the tumor microenvironment. Therefore, CHMP2A not only plays a key role in tumor immune escape, but may also be a target for the development of new therapies.

Fig1. Proposed mechanism of CHMP2A KO in tumor cells. (Davide Bernareggi, 2022)

Bioapplications of CHMP2A

CHMP2A, as part of the ESCRT-III complex, is involved in the formation of autophagosomes during cellular autophagy, which is essential for the removal of damaged proteins and organelles within cells. In addition, CHMP2A is involved in regulating the sensitivity of tumor cells to natural killer (NK) cell-mediated cytotoxicity, and changes in its expression level may affect immune cell activity in the tumor microenvironment, thereby affecting the effectiveness of immunotherapy. In head and neck squamous cell carcinoma, the loss of CHMP2A can increase the sensitivity of tumor cells to NK cells, which provides a potential new target to improve the efficacy of NK cells in tumor therapy. Therefore, CHMP2A has a wide range of applications in biomedical research and clinical therapy, including as a therapeutic target and its potential value in drug development and clinical applications.

Case Study 1: Yoshinori Takahashi, 2018

The process of how phagophores seal to become autophagosomes is not well understood due to challenges in differentiating between open and sealed membranes. However, researchers developed the HaloTag-LC3 assay, which can specifically identify phagophores, early autophagosomes, and mature autophagic structures. Through this assay, they found that CHMP2A, a component of the ESCRT-III complex, plays a key role in closing phagophores. During autophagy, CHMP2A moves to the phagophore and helps separate the inner and outer membranes to create the double-membrane structure of autophagosomes. Additionally, blocking the activity of the VPS4 ATPase enzyme hinders the completion of autophagosomes. This suggests that the ESCRT-driven membrane fission is essential for the formation of functional autolysosomes, ensuring that key lysosomal proteins do not erroneously localize to the inner autophagosomal membrane.

Fig1. CHMP2A translocates to the phagophore in response to nutrient starvation.

Fig2. The SERCA inhibitor thapsigargin further accumulates unclosed autophagosomal membranes in CHMP2A-depleted cells.

Case Study 2: Maryam Alqabandi, 2021

In humans, the ESCRT-III component CHMP2 comes in two forms, CHMP2A and CHMP2B, whose physical properties have not been thoroughly compared. In this study, researchers employed a variety of methods on artificial systems and isolated proteins to examine how these two isoforms interact with and influence membranes. The results showed that CHMP2B's membrane affinity is increased by the presence of PI(4,5)P2 lipids, whereas CHMP2A lacks this lipid preference and needs CHMP3 to effectively bind to membranes. At moderate concentrations, CHMP2B creates a network-like structure on the membrane surface, while CHMP2A combined with CHMP3 binds evenly. Consequently, these two isoforms have distinct impacts on membrane mechanics: CHMP2B makes membranes significantly more rigid, whereas the combination of CHMP2A and CHMP3 does not substantially alter membrane stiffness.

Fig3. Confocal images of 10% PI (4,5)P2-GUVs incubated with CHMP2A.

Fig4. Spinning disk images of supramolecular assemblies of MBP-CHMP2A-ΔC + CHMP3.

CHMP2A has several biochemical functions, for example, phosphatidylcholine binding,protein binding,protein domain specific binding. Some of the functions are cooperated with other proteins, some of the functions could acted by CHMP2A itself. We selected most functions CHMP2A had, and list some proteins which have the same functions with CHMP2A. You can find most of the proteins on our site.

CHMP2A has direct interactions with proteins and molecules. Those interactions were detected by several methods such as yeast two hybrid, co-IP, pull-down and so on. We selected proteins and molecules interacted with CHMP2A here. Most of them are supplied by our site. Hope this information will be useful for your research of CHMP2A.

DOCK8;USP8;USP54;PCBD1;TGFB3;E2F4;1-phosphatidyl-1d-myo-inositol 3,5-bisphosphate;pi3p;midostaurin;Ring1;ATP6AP2;VCAM1;Rab5c;Vps4b;RAB5C