Medical Importance
BID has many implications to humans in health and disease, largely through indirect processes as it is involved in an extremely significant pathway - the apoptotic pathway. Here we outline some examples of the role of BID in disease and its use as a potential therapeutic target.
Role in Ischemia/ Reperfusion
Hepatocytes are protected from undergoing apoptosis following ischemia or reperfusion injury through mutations to BID cleavage sites. Normally, hepatocytes require the cleavage of BID by caspase 8 or granzyme B to undergo apoptosis. It has been shown, following warm reperfusion/ ischaemia reperfusion injury, that rats expressing BID resistant to cleavage in the liver exhibit less hepatocyte apoptosis leading to enhanced functions and survival of the liver [1].
Wei et al.’s gene knockout study [2] also supports BID’s role in ischemia, again using a rodent model, mice, but in kidneys where BID is the most abundant. During ischemia/reperfusion, BID is cleaved (whether the rate is affected is unknown) so that the kidney cells undergo apoptosis like the previous study. They found that BID-deficient mice had significantly lower serum creatinine levels (this tests the kidneys functionality). This suggests BID has a role in ischemic renal injury and failure.
Role of mutations in BID causing disease
A study was carried out to establish the involvement of genetic changes in BID in human cancers. A frameshift and three missense mutations (6.0%) were identified following the analysis of coding region and splice sites of BID gene in 67 progressive gastric carcinomas. It was found that the frequency of apoptosis was substantially reduced in cells with frameshift mutation in BID gene when compared with the wild-type BID gene. The data obtained suggested that the apoptotic function of BID could be lost with a small fraction of mutations [3]
Two polymorphisms in BID have been associated with proteinuria of immunoglobulin A nephropathy (IgAN) from Park et al.’s [4] case-control study involving 195 cases and 289 controls. They analysed 2 single nucleotide polymorphisms (SNPs) in each of BCL2, BID and CASP8 and although associations with IgAN were not found, the SNPs in BID were found to be associated with proteinuria levels of the cases. The minor alleles involved in these SNPs had an additive effect in IgAN patients, where proteinuria levels increased with each copy of the allele. They suggested that BID potentially plays a role in severe IgAN. However, as with any association study, molecular evidence is required to implicate the role of BID in IgAN. Therefore, their conclusion gives good reason to perform appropriate molecular studies.
Role of BID in Tumorigenesis and myeloid homeostasis
It has been indicated that defects in apoptotic pathway involving BID results in myeloid leukemogenesis. As mice lacking BID age, they spontaneously develop a myeloproliferative disorder which advances from myeloid hyperplasia to a fatal, clonal malignancy that highly resembles chronic myelomonocytic leukemia (CMML). The advancement to CMML indicates that BID suppresses tumorigenesis. Further studies are needed to establish whether BID suppresses tumorigenesis in humans in a similar fashion to mice [5].
BID is also required for myeloid homeostasis. This is because BID plays a key role in apoptotic pathway to maintain homeostasis of cell populations in mammals with longer life span [5].
Potential in medical treatments
BID, along with BIM, is a potential target for rheumatoid arthritis (RA) therapy, as suggested in a study by Hutcheson and Perlman [6]. Swelling of joints is characteristic of RA, which is due to the excessive amounts of synovial fibroblasts, lymphocytes, and macrophages [7]. As a result, the expression of Bcl-2, Mcl-1, and Bcl-xl, which are the anti-apoptotic proteins of the Bcl-2 family, in the RA synovium is increased. This suggests that there is a link between these members and the severity of the disease. As BID is pro-apoptotic, synthesising drugs that mimic its effects would be a promising therapeutic option.