Post-translational and transcriptional regulation of peroxisome turnover in health and disease
Descrizione
Peroxisomes are dynamic organelles, which play a crucial role in metabolism, cellular signalling and reactive oxygen species detoxification. Peroxisome turnover is essential to the maintenance of organelle homeostasis and occurs both routinely and in response to external stimuli.
In the last decade, the selective degradation of organelles through autophagy – namely selective autophagy – stood out as a key mechanism for the maintenance of organelle homeostasis. In this regard, peroxisomes are no exception, and their selective degradation through autophagy (i.e. pexophagy) strongly contributes to their turnover and abundance. However, among the selective types of autophagy, pexophagy is probably the least characterised. Through an unbiased phospho-proteomics screening and transcriptomics analysis, we identified novel phosphorylation events targeting peroxisomal proteins, and an autophagy transcription factor which regulates peroxisome related genes. Interestingly, both the post-translational and transcriptional regulations that we discovered may be relevant to pexophagy regulation, and to its coordination with peroxisome biogenesis.
To functionally characterise these newly identified regulatory events, we will rely on golden-standard techniques in the field of genome editing, transcriptomics, and selective reporters and inducers of pexophagy. Because deregulated peroxisome homeostasis has been observed in kidney cancer, we will extend our study to this pathological model. Therefore, we will possibly identify new cancer therapy targets relevant to a subset of kidney cancers.
Finalità
This project has the potential to shed light on the key regulators of pexophagy pathway, dissecting the transcriptional and post-translational events governing its activation. Notably, our discoveries could be relevant for patients affected by a kidney cancer and pave the way for future translational studies aimed at identifying novel and effective therapies.
Risultati attesi
Outcome 1. Functional characterization of phosphorylation sites and protein-protein interacting motifs of selective pexophagy receptors.
Outcome 2. Functional characterization of phosphorylation sites of selective regulators of pexophagy and peroxisome biogenesis.
Outcome 3. Characterization of the transcriptional co-regulation of pexophagy and peroxisome biogenesis.
Outcome 4. Characterization of pexophagy relevance in kidney cancer.
Stato dell’arte
Peroxisomes are dynamic organelles essential for metabolism, cellular signaling, and detoxification of reactive oxygen species (ROS). Their homeostasis relies on a balance between biogenesis and degradation, with pexophagy playing a key role in peroxisome turnover. Pexophagy occurs both routinely and in response to stressors such as hypoxia, starvation, iron depletion, and ROS accumulation. However, the molecular mechanisms regulating pexophagy remain poorly understood, and most studies focus on starvation-induced pathways, leaving other regulatory mechanisms largely unexplored.
Recent findings suggest that peroxisome homeostasis may be linked to disease, including kidney cancer. While never directly investigated, a transcriptional layer of regulation likely coordinates peroxisome biogenesis and degradation, as seen in mitophagy. Understanding these regulatory networks and their impact on cellular metabolism could provide new insights into disease mechanisms and potential therapeutic strategies.
Riferimento: PRIN 2022 PNRR – Codice progetto: P2022TJZYZ – CUP: F53D23008670001
Investimento totale del progetto: € 279.916
Partner/proponente: Università degli Studi Roma TRE (Coordinatore), Università degli Studi di Napoli Federico II
Coordinatore dell’UdR Università degli Studi Roma Tre: Dott.ssa Valentina Cianfanelli
