IMCB’s latest PhD Graduate - Umayal Lakshmanan
I showed that human caspase-4 contributes to apoptosis induced by ER (endoplasmic reticulum) stressors such as brefeldin A, a calcium ionophore and thapsigargin. An expansion of polyglutamine tracts is an underlying mutational mechanism of several neurodegenerative diseases; and aggregates of expanded polyglutamine [polyQ]-containing proteins are a prominent pathological characteristic of polyglutamine diseases like SBMA, Huntington’s, DRPLA and Spino-Cerebellar-Ataxia. Employing a human neuronal cell line, I also showed that caspase-4 plays a role in ER stress caused by polyQ-72 aggregates. Hence caspase-4 may have a role in the pathogenesis of disorders caused by expansion of an unstable CAG triplet.
During Gram-negative infections, the innate immune response is activated by bacterial LPS acting on Toll-Like-Receptor-4. TLR4 engages a multi-protein complex to activate transcription factors that up-regulate various inflammatory cytokines and chemotactic chemokines. I found that upon LPS stimulation, caspase-4 forms a transient complex with TRAF6 and IRAK1 through a conserved TRAF6-binding site I identified in caspase-4, leading to NF-κB activation. This is required for the transcription and secretion of various cytokines and chemokines, including IL-8 (inflammation, motogenesis, angiogenesis), IL-1β
(inflammation, fever) and CCL4 (chemoattraction of immune cells), which together contribute to innate immune and inflammatory responses. I found that caspase-4 is required to produce a substantial proportion of IL-8, IL-1β and CCL4 in the culture supernatant of a human monocytic cell line following LPS stimulation.
Published in Journal of Immunology 179, 8480 (2007).