NF-kB

By Jamshed Arslan Pharm.D.

In the first installment of this two-part blog post titled "Apoptosis and Necroptosis: Important factors to identify both types of programmed cell death", the mechanisms by which cell death occurs and ways to identify these pathways were discussed. In this next segment, we focus on the molecular factors regulating the choice between programmed cell death and survival signaling.

RelA (also known as p65) is an NF-kB family member and a subunit of the NF-kB transcription factor complex.  The mammalian NF-kB family has five members (NF-kB1, NF-kB2, RelA (p65), RelB, and c-Rel), each of which contains an N-terminal Rel homology domain. Active NF-kB protein complexes are dimeric (hetero- or homo-), and are made up of two family members. NF-kB signaling is activated in response to many different types of stimuli and modulates transcription of numerous downstream targets.

Apoptosis, also called programmed cell death, is an essential process in development and disease. The signaling networks that carry out apoptosis is consists of a series of endoproteases called caspases which are synthesized as inactive zymogens. Caspses are grouped into two classes: initiator caspases and effector caspases. Initiator caspases are activated by the assembly of multi-protein complexes such as the death-inducing signaling complex (DISC) (1).

Protein kinase R (PKR) is an intracellular stress-sensing protein that is able to detect and respond to viral infections. While PKR is able to sense and respond to a variety of signals, dsRNA is a well-characterized ligand. dsRNA produced during viral replication binds to PKR and induces a conformational change, dimerization, and exposure of the catalytic autophosphorylation site (1). Once in this active form PKR is able to phosphorylate substrates to regulate cell growth and stress responses.

By: Subhash Gangar

Thrombomodulin, also known as BDCA-3, is a glycosylated transmembrane protein present on the surface of vascular endothelial cells. Thrombomodulin is a high-affinity receptor for thrombin, a key protein in the coagulation cascade. Formation of the thrombomodulin-thrombin complex blocks the thrombin dependent conversion of fibrinogen to fibrin and also catalyzes the activation of protein C. Active protein C is able to proteolytically inactivate enhancers of the coagulation cascade.

The inhibitor of apoptosis proteins (IAPs) are important regulators of cell death and inflammation. The cellular inhibitor of apoptosis protein 2 (cIAP2) contains three Baculovirus IAP repeat (BIR) domains, a Ubiquitin associated (UBA) domain, and a RING domain with E3 ligase activity. cIAP2 inhibits apoptosis through direct inhibition of the pro-apoptotic caspase-3. cIAP2 also regulates cell survival through its role in the tumor necrosis factor alpha (TNF-alpha) signaling pathway.

IL-33 is a member of the interleukin family of cytokines that regulates a wide variety of cellular functions. Its receptor is ST2, an IL-1 receptor family member that also acts as a negative regulator of TLR-IL-1R signaling and the IL-1R accessory protein (IL-1RAcP). Receptor binding of IL-33 activates NF-kB and MAP kinases, stimulating downstream expression of TH2-associated cytokines such as IL-4, IL-5 and IL-6.

TNF alpha is a multifunctional proinflammatory cytokine that belongs to the tumor necrosis factor (TNF)-receptor superfamily. It is involved in the regulation of a wide spectrum of biological processes: cell proliferation, differentiation, apoptosis, inflammation, lipid metabolism, and coagulation. TNF alpha has been implicated in a variety of autoimmune diseases (rheumatoid arthritis, Crohn's disease, multiple sclerosis, and psoriasis), insulin resistance, septic shock, and tumor metastases related to cancer.