ATG2B (Autophagy-related 2B)

2016-10-01   Christine Bellanné-Chantelot , Isabelle Plo 

Identity

HGNC
LOCATION
14q32.2
LOCUSID
ALIAS
C14orf103
FUSION GENES

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)

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.

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
Familial myeloproliferative neoplasms (MPN)
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
The percentage of transformation is close to 50% in these familial MPN cases and is related to the detection of mutations affecting epigenetic regulator genes such as TET2 IDH1 or IDH2.
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).

Bibliography

Pubmed IDLast YearTitleAuthors
191979482009Frameshift mutations of autophagy-related genes ATG2B, ATG5, ATG9B and ATG12 in gastric and colorectal cancers with microsatellite instability.Kang MR et al
177123582007Autophagy: from phenomenology to molecular understanding in less than a decade.Klionsky DJ et al
262809002015Germline duplication of ATG2B and GSKIP predisposes to familial myeloid malignancies.Saliba J et al
222193742012Mammalian 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 IDTranscript IDUniprot
ENSG00000066739ENST00000359933Q96BY7

Expression (GTEx)

0
5
10
15
20
25
30

Pathways

PathwaySourceExternal ID
Autophagy - animalKEGGko04140
Autophagy - animalKEGGhsa04140
Autophagy - otherKEGGko04136
Autophagy - otherKEGGhsa04136

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
222193742012Mammalian Atg2 proteins are essential for autophagosome formation and important for regulation of size and distribution of lipid droplets.120
191979482009Frameshift mutations of autophagy-related genes ATG2B, ATG5, ATG9B and ATG12 in gastric and colorectal cancers with microsatellite instability.63
223504152012miRNA-130a targets ATG2B and DICER1 to inhibit autophagy and trigger killing of chronic lymphocytic leukemia cells.63
253229402015miR-143 inhibits cell proliferation by targeting autophagy-related 2B in non-small cell lung cancer H1299 cells.25
262809002015Germline duplication of ATG2B and GSKIP predisposes to familial myeloid malignancies.23
288001312017Atg2A/B deficiency switches cytoprotective autophagy to non-canonical caspase-8 activation and apoptosis.20
272650292016Aberrant methylation of ATG2B, ATG4D, ATG9A and ATG9B CpG island promoter is associated with decreased mRNA expression in sporadic breast carcinoma.5
295622742018MicroRNA-143 Targets ATG2B to Inhibit Autophagy and Increase Inflammatory Responses in Crohn's Disease.3
279605882018Investigation of Association between Autophagy-Related Gene Polymorphisms and Pseudoexfoliation Syndrome and Pseudoexfoliation Glaucoma in a Spanish Population.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)