PIDD1 in cell cycle control, sterile inflammation and cell death

Abstract

The death fold domain-containing protein PIDD1 has recently attracted renewed attention as a regulator of the orphan cell death-related protease, Caspase-2. Caspase-2 can activate p53 to promote cell cycle arrest in response to centrosome aberrations, and its activation requires formation of the PIDDosome multi-protein complex containing multimers of PIDD1 and the adapter RAIDD/CRADD at its core. However, PIDD1 appears to be able to engage with multiple client proteins to promote an even broader range of biological responses, such as NF-κB activation, translesion DNA synthesis or cell death. PIDD1 shows features of inteins, a class of self-cleaving proteins, to create different polypeptides from a common precursor protein that allow it to serve these diverse functions. This review summarizes structural information and molecular features as well as recent experimental advances that highlight the potential pathophysiological roles of this unique death fold protein to highlight its drug-target potential.

Aberrant centrosome biogenesis disrupts nephron progenitor cell renewal and fate resulting in fibrocystic kidney disease

“…One possibility is that components of the mitotic surveillance pathway are differentially expressed in the nephron progenitor stage compared to differentiated tubular cells, such that the pathway is only activated in progenitors. Indeed, our RNAseq analyses indicate that activators of the p53-mediated surveillance pathway (e.g., Pidd1, 74,75 ) were highly upregulated upon centrosome loss during the progenitor cell stage (E13.5, Figure 4), but were not differentially expressed in fully differentiated tubular cells at P15. Conversely, the expression of inhibitors of the p53-mediated pathway (e.g., Mdm2, 76 ) were downregulated in centrosome-less cells during embryonic stages, but the expression was high in postnatal differentiated epithelial cells (Supplementary Excel 2).…”

Cellular and molecular basis of therapeutic approaches to breast cancer

“…Understanding how chemicals work to stop or interrupt the cell cycle necessitates a thorough understanding of the cycle itself. The cycle is divided into stages or phases by specific occurrences, with checkpoints at each stage [25]. The first checkpoint prevents the cell from advancing past the G1 phase, which happens between the G1 and S (synthetic) phases [26].…”

“…The cell is stated to be in the G2 phase after DNA synthesis until it crosses the G2/M checkpoint, at which time it enters prophase [25,29]. At this time in the cell cycle, centrosomes migrate to form the cell's two poles.…”

“…At this time in the cell cycle, centrosomes migrate to form the cell's two poles. Microtubules are composed of tubulin molecules that break down and rebuild to orient cellular components at various stages, including chromosomes and their associated proteins during mitosis [25,29]. Numerous drugs can interfere with this process, and their use in chemotherapy is justified by the fact that cells that cannot replicate mitotically without this microtubule system functioning properly will eventually die, and the cells that go through these processes are those that divide quickly, including cancer cells [44].…”

Protein supersaturation powers innate immune signaling

“…These are also atypical in their having a finite oligomeric rather than polymeric structure ( 67, 68 ), which emphasizes the dependence of nucleation barriers on semi-crystalline ordering. These two signalosomes are also exceptional from a functional perspective— they respond exclusively to cell-intrinsic signals of stress rather than extrinsic signals of infection ( 69, 70 ). Hence their functions do not require the extreme sensitivity that nucleation barriers hypothetically offer.…”