Nuclear TP53: An unraveled function as transcriptional repressor of PINK1

ABSTRACT

The tumor suppressor TP53/p53 is a key protein in both neurodegenerative diseases and cancer. Thus, TP53-linked cell death appears exacerbated in several age-related neuropathologies, while TP53 mutation-associated phenotypes indicate a loss of function accounting for approximately half of cancers. Thus, TP53 plays a pivotal role in these phenotypically distinct pathologies, a hypothesis reinforced by recent epidemiological studies suggesting an opposite risk to develop one type of pathology relative to the other. Dysfunctions in mitophagic processes also occur in both types of pathologies and again, TP53 has been proposed as one of the regulators of this cellular process. The consensus view postulates that TP53 exerts both anti- and pro-autophagy functions that are directly driven by a specific subcellular localization. Thus, TP53 positively modulates autophagy via the transcriptional control of several genes while it is acknowledged that its anti-autophagy phenotype is exclusively linked to a transcription-independent cytosolic control of an AMPK-MTOR cascade. Our study indicates that TP53 can also downregulate the specialized autophagy-related mitophagy response via the transcriptional repression of PINK1. This is the first demonstration of an anti-mitophagic control by nuclear TP53.

Age-related diseases are major health problems in Western societies. Epidemiological studies indicate that the risk of developing Alzheimer and Parkinson diseases is reduced in patients affected by a subset of cancers. Intuitively, this suggests that cellular factors, the function of which would be exacerbated during the cell death process, could be functionally altered in tumorigenesis. One of the candidates fulfilling this key role could be TP53. TP53 is a tumor suppressor, the mutations of which account for approximately 50% of cancers. Mutations of TP53 trigger a loss of its transcription factor properties that directly affects its ability to control cell proliferation and apoptosis. Conversely, several studies consistently document an enhanced TP53-dependent cell death in Parkinson disease (PD). Interestingly, several works also indicate that TP53-dependent apoptotic cells are detectable in restricted areas in Alzheimer disease (AD)-affected brains. Overall, these observations suggest the existence of a balanced shift between the two types of pathologies during ageing.

Genetic clues brought significant support to a key role of TP53 in neurodegenerative pathologies. Mutations in various genes that account for most of the autosomal dominant (AD and PD) or recessive (PD) cases have been identified. Mutations in PSEN1 and PSEN2 or APP (amyloid beta precursor protein) are responsible for aggressive and early-onset AD. In PD, numerous studies have identified PD-linked candidates that are, among others, SNCA/α-synuclein, PRKN/parkin and PINK1 (PTEN induced putative kinase 1). Strikingly, all of the above-described mutated proteins modulate, either positively or negatively, the expression and transcriptional function of TP53. Of note, TP53 also affects expressions of these proteins, suggesting that there exists a feedback control interplay between TP53 and its targets that drives protein homeostasis, and that it could be disrupted in pathological conditions.

Of interest, several papers indicated that in cancer conditions, expression of the above-cited proteins are affected. As a significant example, we were able to show that PRKN expression is reduced in a grade-dependent manner in gliomas and that this is due to a loss of function of TP53. Overall, these observations underlie an intricate dialog between proteins involved in neurodegenerative diseases and TP53.

Another anatomical stigma consistently observed in both neurodegenerative diseases and tumors is a drastic dysfunction in the autophagy process. Again, TP53 has been documented as a key modulator of the autophagic response. At a glance, the involvement of TP53 is complex and somewhat puzzling as it can trigger both pro- and anti-autophagic processes. These paradoxical observations are apparently explained by TP53 subcellular localization and associated function. Thus, TP53 elicits a pro-autophagic phenotype mainly in stress conditions by means of its transcription factor ability to modulate genes involved in the control of MTOR (mechanistic target of rapamycin kinase), DAPK1 (death associated protein kinase 1) and DRAM (DNA damage regulated autophagy modulator). Conversely, the TP53-dependent anti-autophagic phenotype is exclusively accounted for by cytoplasmic TP53, which triggers transcription-independent activation of the AMPK-dependent blockade of MTOR signaling. The above observations led to the assumption that nuclear TP53 could only be involved in a pro-autophagic function.

In our recent study, 4 distinct lines of evidence clearly indicate that the transcriptional function of TP53 can also trigger an anti-mitophagic phenotype. First, TP53 represses PINK1 protein and mRNA expression and reduces PINK1 promoter transactivation in cells as well as in vivo. Second, we identified a TP53-responsive element in the promoter of PINK1, the mutation of which significantly reduces TP53-dependent PINK1 promoter activity. Third, TP53 gene invalidation increases expression of the autophagy receptors OPTN (optineurin) and CALCOCO2/NDP52 and the generation of LC3-II, and concomitantly reduces TIMM23, TOMM20 and HSPD1/HSP60 mitophagy markers in cells as well as in mice brain. Fourth, pifithrin-α, a blocker of TP53 transcription function, mimics TP53 gene invalidation, a phenotype fully abolished by PINK1 depletion. Overall, our study is the first demonstration that nuclear TP53 can behave as an anti-mitophagic effector by transcriptional repression of PINK1. This also explains, at least in part, why when TP53 is translocated to the nucleus, this ultimately leads to PINK1 decreased expression and reduced mitophagy. This process can be antagonized by PRKN-induced reduction of TP53 activity (see discussion below and Figure 1).

Figure 1.

Interplay between TP53 and PINK1 to control mitophagy. Nuclear TP53 represses PINK1 transcription to induce an anti-mitophagic process. When TP53 is translocated to the nucleus, it decreases PINK1 transcription. Reduction of PINK1 leads to reduced mitophagy illustrated by decreased expression of OPTN, CALCOCO2 and LC3-II and concomitant increases of SQSTM1/p62, TIMM (TIMM23), TOMM (TOMM20) and HSPD1/HSP60. ub, ubiquitin.

The regulation of PINK1 is complex. Thus, we showed previously that PRKN represses TP53 at a transcriptional level. We also recently demonstrated that PRKN controls PINK1 and its associated phenotypes via direct transcriptional modulation of PSEN (presenilin). These data underlie the fact that TP53-related control of PINK1 could occur via distinct pathways either dependent on or independent of PRKN.

Of most interest, recent studies from the University of California, Los Angeles, and Beijing University (Liu and colleagues) demonstrated that PINK1, which behaves as a kinase, phosphorylates TP53 and that this phosphorylation enhances TP53 translocation to the nucleus. As a consequence, the mitophagic process is impaired. This set of data could be seen as a feedback loop where PINK1 activates TP53 by phosphorylation. Thus, upon various cellular challenges or stresses, phosphorylated TP53 would be translocated into the nucleus, leading to PINK1 transcriptional reduction, which in turn would reduce TP53 phosphorylation and subsequent translocation to the nucleus. This could be seen as a beneficial cellular mechanism avoiding drastic deleterious effects of TP53-dependent PINK1 downregulation and, thus, an unnecessary sustained anti-mitophagic process.

We wish to acknowledge the contributions of all authors appearing on the original article. This work was supported by the ‘Conseil départemental des Alpes Maritimes’ and the Foundation Claude Pompidou. This work has been developed and supported through the LABEX (excellence laboratory, program investment for the future) DISTALZ (Development of Innovative Strategies for a Transdisciplinary approach to Alzheimer'disease) and the Hospital University Federation (FHU) OncoAge. Thomas Goiran has been funded by the Ligue Contre le Cancer.

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.