Abstract
Autophagy is a cellular process involved in the sequestration of cytosolic components and their degradation by lysosomes. Autophagy has been involved in physiological responses to stress or aging and in the development of many human diseases including solid and haematological cancers. In humans, 16 autophagy-related genes are known. The ATG2B protein is involved in the late steps of the autophagy process i.e. the formation of autophagosomes that fuse with lysosomes before degradation. Loss-of -function (frameshift) acquired mutations of ATG2B have been identified in gastric and colorectal carcinomas with high microsatellite instability. Both pharmacologic and genetic evidence indicate that autophagy plays pleiotropic functions in hematopoietic cell homeostasis and leukemogeneis. Autophagy could exert two opposite roles (cell death and survival) depending on the nature of the hematopoietic malignancy.
DNA/RNA
Description
The ATG2B gene consists of 42 exons spanning a region of 82.08 kb.
Transcription
A single mRNA transcript (NM_018036.6) of the ATG2B gene, with a total length of 6234 nucleotides, has been annotated.
Pseudogene
Not yet identified.
Proteins
Description
The protein encoded by the ATG2B gene is the autophagy-related protein 2 homolog B of 2078 amino acids, with a calculated molecular mass of 232.8 kDa
Expression
Expression of ATG2B has been detected in various normal human tissues (bone marrow, whole blood, thymus, brain, heart, muscle, colon, kidney, liver, lung, pancreas, thyroid, salivary and adrenal glands, skin, ovary, uterus, placenta, prostate and testis).
In hematopoietic cells, ATG2B is expressed in CD34+ purified hematopoietic progenitors and CD36+ erythroblasts or CD41+ megakaryocytes derived from CD34+ progenitors cultured in vitro (Saliba et al, 2016)
In hematopoietic cells, ATG2B is expressed in CD34+ purified hematopoietic progenitors and CD36+ erythroblasts or CD41+ megakaryocytes derived from CD34+ progenitors cultured in vitro (Saliba et al, 2016)
Localisation
ATG2B is mainly localized in the nucleus.
Function
Autophagy is an intracellular degradation system by which cytoplasmic materials are enclosed by the autophagosomes and transferred to lysosomes before degradation. The autophagy process has been extensively studied in yeast; 35 autophagy-related genes (ATG) have been identified, of which 16 are currently known in humans . This cellular process is a highly conserved among species. In humans, two ATG2 proteins, ATG2A and ATG2B, have redundant functions and are required for autophagosome formation (Velikkakath AK et al , 2012).
Homology
44.5% of human ATG2B residues are identical to those of human ATG2A.
Mutations
Germinal
A germline 14q32.2 head-to-tail duplication of 700 kb has been associated with familial myeloid malignancies (Saliba et al , 2015). The germline duplication includes the genes TCL1A, GSKIP, ATG2B, BDKRB1, BDKRB2 and the first exon of AK7. The overexpression of ATG2B and GSKIP that are expressed in myeloid cells, enhances hematopoietic progenitor differentiation, particularly of megacaryocytes. The development of myeloid malignancies required the cooperation of both genes with the myeloproliferative neoplasms (MPN) driver JAK2 Val617Phe mutation, MPL or CALR mutations. The mechanism of cooperation between ATG2B and GSKIP with MPN driver mutations remains unknown.
The germline duplication with the same distal and proximal breakpoints has only been identified in MPN families originated from West Indies (Martinique) suggesting a founder effect.
The germline duplication with the same distal and proximal breakpoints has only been identified in MPN families originated from West Indies (Martinique) suggesting a founder effect.
Somatic
A loss-of-function somatic mutation (c.3120delA, p.Lys1040fs) in gastric carcinomas (15.6%) and in colorectal carcinomas (11.6%) (Klionsky DJ, 2009).
Implicated in
Entity name
Disease
Familial MPN, in particular, essential thrombocythemia progressing to myelofibrosis and/or acute myeloid leukemia and primary myelofibrosis, with autosomal dominant inheritance and originated from West-indies (Martinique) may be linked to ATG2B/GSKIP germline duplication. The predisposition is highly penetrant (80%) and is characterized by an earlier age of MPN onset in comparison to sporadic cases (41 years versus > 60 years). The spectrum of acquired driver mutations (JAK2 Val617Phe, MPL and CALR mutations) is similar to the spectrum of mutations in sporadic MPN cases.
Prognosis
Entity name
Acute myeloid leukemia (AML)
Disease
AML originated from West-indies (Martinique) may be linked to ATG2B/GSKIP germline duplication.
Prognosis
The prognosis of the disease is also linked to the detection of acquired mutations in TET2, IDH1 or in IDH2. No TP53 mutation was found, contrary to what was observed in AML evolving from MPN, suggesting a different pathway for leukemic transformation.
Entity name
Gastric carcinoma
Note
Loss-of-functions somatic mutations in ATG genes (ATG2B, ATG5, ATG9B and ATG12) are identified in 28% of gastric carcinomas with high microsatellite instability. These mutations may contribute to cancer development by deregulating the autophagy process (Kang et al, 2009).
Entity name
Colorectal cancer
Note
Loss-of-functions somatic mutations in ATG genes (ATG2B, ATG5, ATG9B and ATG12) are identified in 28% of colorectal carcinomas with high microsatellite instability. These mutations may contribute to cancer development by deregulating the autophagy process (Kang et al, 2009).
Article Bibliography
| Pubmed ID | Last Year | Title | Authors |
|---|---|---|---|
| 19197948 | 2009 | Frameshift mutations of autophagy-related genes ATG2B, ATG5, ATG9B and ATG12 in gastric and colorectal cancers with microsatellite instability. | Kang MR et al |
| 17712358 | 2007 | Autophagy: from phenomenology to molecular understanding in less than a decade. | Klionsky DJ et al |
| 26280900 | 2015 | Germline duplication of ATG2B and GSKIP predisposes to familial myeloid malignancies. | Saliba J et al |
| 22219374 | 2012 | Mammalian Atg2 proteins are essential for autophagosome formation and important for regulation of size and distribution of lipid droplets. | Velikkakath AK et al |
Other Information
Locus ID:
NCBI: 55102
MIM: 616226
HGNC: 20187
Ensembl: ENSG00000066739
Variants:
dbSNP: 55102
ClinVar: 55102
TCGA: ENSG00000066739
COSMIC: ATG2B
RNA/Proteins
| Gene ID | Transcript ID | Uniprot |
|---|---|---|
| ENSG00000066739 | ENST00000359933 | Q96BY7 |
Expression (GTEx)
Pathways
| Pathway | Source | External ID |
|---|---|---|
| Autophagy - animal | KEGG | ko04140 |
| Autophagy - animal | KEGG | hsa04140 |
| Autophagy - other | KEGG | ko04136 |
| Autophagy - other | KEGG | hsa04136 |
Protein levels (Protein atlas)
References
| Pubmed ID | Year | Title | Citations |
|---|---|---|---|
| 38866787 | 2024 | Human gastric cancer progression and stabilization of ATG2B through RNF5 binding facilitated by autophagy-associated CircDHX8. | 0 |
| 38866787 | 2024 | Human gastric cancer progression and stabilization of ATG2B through RNF5 binding facilitated by autophagy-associated CircDHX8. | 0 |
| 34172895 | 2022 | Germline ATG2B/GSKIP-containing 14q32 duplication predisposes to early clonal hematopoiesis leading to myeloid neoplasms. | 8 |
| 34748402 | 2022 | Loss of Atg2b and Gskip Impairs the Maintenance of the Hematopoietic Stem Cell Pool Size. | 2 |
| 35902797 | 2022 | The prognostic value of autophagy related genes with potential protective function in Ewing sarcoma. | 4 |
| 34172895 | 2022 | Germline ATG2B/GSKIP-containing 14q32 duplication predisposes to early clonal hematopoiesis leading to myeloid neoplasms. | 8 |
| 34748402 | 2022 | Loss of Atg2b and Gskip Impairs the Maintenance of the Hematopoietic Stem Cell Pool Size. | 2 |
| 35902797 | 2022 | The prognostic value of autophagy related genes with potential protective function in Ewing sarcoma. | 4 |
| 33250346 | 2021 | Polymorphism in autophagy gene ATG2B is not associated with bladder cancer recurrence after intravesical Bacillus Calmette-Guerin (BCG) immunotherapy in Asian patients. | 0 |
| 33554699 | 2021 | ATG2B/GSKIP in de novo acute myeloid leukemia (AML): high prevalence of germline predisposition in French West Indies. | 2 |
| 33760149 | 2021 | miR‑143‑3p inhibits endometriotic stromal cell proliferation and invasion by inactivating autophagy in endometriosis. | 13 |
| 33824300 | 2021 | LncRNA-HOTAIR activates autophagy and promotes the imatinib resistance of gastrointestinal stromal tumor cells through a mechanism involving the miR-130a/ATG2B pathway. | 25 |
| 34320900 | 2021 | Crocin exerts anti-proliferative and apoptotic effects on cutaneous squamous cell carcinoma via miR-320a/ATG2B. | 9 |
| 34695177 | 2021 | Downregulation of LINC01296 suppresses non-small-cell lung cancer via targeting miR-143-3p/ATG2B. | 6 |
| 33250346 | 2021 | Polymorphism in autophagy gene ATG2B is not associated with bladder cancer recurrence after intravesical Bacillus Calmette-Guerin (BCG) immunotherapy in Asian patients. | 0 |
Citation
Christine Bellanné-Chantelot ; Isabelle Plo
ATG2B (Autophagy-related 2B)
Atlas Genet Cytogenet Oncol Haematol. 2016-10-01
Online version: http://atlasgeneticsoncology.org/gene/55326/atg2b-(autophagy-related-2b)
