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Review
. 2023 Jun;30(6):1437-1446.
doi: 10.1038/s41418-023-01158-5. Epub 2023 Apr 8.

BCL-G: 20 years of research on a non-typical protein from the BCL-2 family

Mariusz L Hartman  1 , Malgorzata Czyz  2
Affiliations
Review

BCL-G: 20 years of research on a non-typical protein from the BCL-2 family

Mariusz L Hartman et al. Cell Death Differ. 2023 Jun.

Abstract

Proteins from the BCL-2 family control cell survival and apoptosis in health and disease, and regulate apoptosis-unrelated cellular processes. BCL-Gonad (BCL-G, also known as BCL2-like 14) is a non-typical protein of the family as its long isoform (BCL-GL) consists of BH2 and BH3 domains without the BH1 motif. BCL-G is predominantly expressed in normal testes and different organs of the gastrointestinal tract. The complexity of regulatory mechanisms of BCL-G expression and post-translational modifications suggests that BCL-G may play distinct roles in different types of cells and disorders. While several genetic alterations of BCL2L14 have been reported, gene deletions and amplifications prevail, which is also confirmed by the analysis of sequencing data for different types of cancer. Although the studies validating the phenotypic consequences of genetic manipulations of BCL-G are limited, the role of BCL-G in apoptosis has been undermined. Recent studies using gene-perturbation approaches have revealed apoptosis-unrelated functions of BCL-G in intracellular trafficking, immunomodulation, and regulation of the mucin scaffolding network. These studies were, however, limited mainly to the role of BCL-G in the gastrointestinal tract. Therefore, further efforts using state-of-the-art methods and various types of cells are required to find out more about BCL-G activities. Deciphering the isoform-specific functions of BCL-G and the BCL-G interactome may result in the designing of novel therapeutic approaches, in which BCL-G activity will be either imitated using small-molecule BH3 mimetics or inhibited to counteract BCL-G upregulation. This review summarizes two decades of research on BCL-G.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Domain structure of BCL-G and expression of BCL2L14 in human tissues and organs.
A Amino acid sequences of human long and short isoforms of BCL-G: BCL-GL and BCL-GS, respectively were obtained from uniprot.org. The BH3 domain (amino acids from 212 to 226) and BH2 domain (amino acids from 308 to 315) are marked. B Upper panel: Transcript levels of BCL2L14 were assessed by RNA sequencing in different human tissues and organs (BioProject dataset, study PRJEB4337 including samples from 95 individuals representing 27 different tissues, also published [117]; and PRJEB2445 involving 16 tissue samples). Lower panel: Transcript levels of BCL2L14 were assessed by RNA sequencing in different human fetal tissues between the 10th and 20th weeks of fetal development (BioProject dataset, study PRJNA270632 including 35 human fetal samples from 6 tissues, also published [118]). RPKM reads per kilobase of transcript per million reads mapped.
Fig. 2
Fig. 2. Positive and negative regulators of BCL-G level and activity.
In transcriptional regulation, activators are marked in green, while transcriptional repressors are shown in red. For interaction with JAB1, BCL-GS was shown to be relocated from the association with either BCL-XL or BCL-2 [46]. Dotted lines are used to show indirect influence. The phosphorylation sites of human BCL-G were retrieved from www.phosphosite.org.
Fig. 3
Fig. 3. A timeline of major milestones in BCL-G investigation.
Discoveries made using state-of-the-art genetic manipulation approaches and complementary methods to validate the role of BCL-G are framed.
See this image and copyright information in PMC

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