Uncovering the PIDDosome and caspase-2 as regulators of organogenesis and cellular differentiation

Abstract

The PIDDosome is a multiprotein complex that drives activation of caspase-2, an endopeptidase originally implicated in apoptosis. Yet, unlike other caspases involved in cell death and inflammation, caspase-2 seems to exert additional versatile functions unrelated to cell death. These emerging roles range from control of transcription factor activity to ploidy surveillance. Thus, caspase-2 and the PIDDosome act as a critical regulatory unit controlling cellular differentiation processes during organogenesis and regeneration. These newly established functions of the PIDDosome and its downstream effector render its components attractive targets for drug-development aiming to prevent fatty liver diseases, neurodegenerative disorders or osteoporosis. Facts • Caspase-2 and the PIDDosome are involved in the differentiation of various cell types. • Caspase-2, PIDD1 and RAIDD have roles outside the PIDDosome. • Caspase-2 has nonapoptotic functions.

Biallelic mutations in the death domain of PIDD1 impair caspase-2 activation and are associated with intellectual disability

“…Several reports implicate caspase-2 in neuronal cell death caused by NGF or beta-amyloids 8,14 . Whether these effects of caspase-2 require PIDDosome formation remains less clear 15 . Caspase-2 can also process tau protein leading to its accumulation in dendritic spines, which have been found to be increased in cognitively impaired mice and humans 16 .…”

The p53-caspase-2 axis in the cell cycle and DNA damage response

“…2 ). Caspase-2 is also recruited to a large multiprotein complex called the PIDDosome 28 (see below). Caspase-2 is the only caspase with a classical nuclear localization signal that mediates its predominant localization to the nucleus 29 .…”

AIEgen‐enhanced protein imaging: Probe design and sensing mechanisms

“…Recent research has demonstrated that some have potential in developing drugs aimed at preventing osteoporosis, fatty liver diseases, or neurodegenerative disease. [60][61][62] Ding et al [47] have synthesized a fluorescent bioprobe containing two peptides, caspase-specific Asp-Glu-Val-Asp (Ac-DEVD) and cRGD, onto TPS units. While the fluorescence intensity of this probe remarkably increased in the presence of caspase-3, however, the probe was not emissive in aqueous solutions.…”

“…Recent research has demonstrated that some have potential in developing drugs aimed at preventing osteoporosis, fatty liver diseases, or neurodegenerative disease. [ 60–62 ] Ding et al . [ 47 ] have synthesized a fluorescent bioprobe containing two peptides, caspase‐specific Asp‐Glu‐Val‐Asp (Ac‐DEVD) and cRGD, onto TPS units.…”