iPCD: A Comprehensive Data Resource of Regulatory Proteins in Programmed Cell Death

Abstract

Programmed cell death (PCD) is an essential biological process involved in many human pathologies. According to the continuous discovery of new PCD forms, a large number of proteins have been found to regulate PCD. Notably, post-translational modifications play critical roles in PCD process and the rapid advances in proteomics have facilitated the discovery of new PCD proteins. However, an integrative resource has yet to be established for maintaining these regulatory proteins. Here, we briefly summarize the mainstream PCD forms, as well as the current progress in the development of public databases to collect, curate and annotate PCD proteins. Further, we developed a comprehensive database, with integrated annotations for programmed cell death (iPCD), which contained 1,091,014 regulatory proteins involved in 30 PCD forms across 562 eukaryotic species. From the scientific literature, we manually collected 6493 experimentally identified PCD proteins, and an orthologous search was then conducted to computationally identify more potential PCD proteins. Additionally, we provided an in-depth annotation of PCD proteins in eight model organisms, by integrating the knowledge from 102 additional resources that covered 16 aspects, including post-translational modification, protein expression/proteomics, genetic variation and mutation, functional annotation, structural annotation, physicochemical property, functional domain, disease-associated information, protein-protein interaction, drug-target relation, orthologous information, biological pathway, transcriptional regulator, mRNA expression, subcellular localization and DNA and RNA element. With a data volume of 125 GB, we anticipate that iPCD can serve as a highly useful resource for further analysis of PCD in eukaryotes.

Keywords: GPX4; PCD protein; apoptosis; ferroptosis; programmed cell death.

Figure 1

The procedure for the construction of iPCD and the comparison between iPCD and 12 additional databases. (A) The workflow for the construction of the iPCD database. First, we collected 30 experimentally identified forms of PCD proteins from PubMed and annotated them ‘+’ or ‘−’ as positive or negative PCD regulator. Then, 11 additional PCD databases were merged and carefully re-curated for each entry, and further conducted an orthologous search to computationally identify new PCD regulators in 562 eukaryotes. Next, the PCD regulators were annotated with 102 additional public resources in 8 model organisms that covered 16 aspects. (B) The numbers of PCD proteins included in iPCD and 13 additional databases.

Figure 2

The data statistics of PCD regulators in the iPCD. (A) The numbers of PCD regulations and computationally identified PCD regulators are shown according to classification. (B) The distribution of experimentally identified PCD regulators in 8 model organisms. (C) The percentage distribution of experimentally identified PCD regulators in 8 model organisms. (D) The numbers of PCD forms in 8 model organisms.

Figure 3

The data counts and analysis of PCD regulators in the iPCD. (A) The numbers of positive regulators (‘+’), negative regulators (‘−’) and dual regulators (‘+/−’) are separately presented for each PCD form. (B) The overlap of two types human PCD regulators. (C) The numbers of PCD regulators involved in different PCD forms. (D) The GO-based enrichment analysis of regulators involved in more than 2 PCD processes.

Figure 4

The usage of browse options in the iPCD. (A) Browse by process. (B) Browse by species. (C) The basic information page of human GPX4. Additional annotations could be viewed by clicking the ‘Annotation’ or ‘Integrated Annotations’. (D) The additional annotations page of human GPX4 covered 16 aspects. The detailed PTM information of PLMD about GPX4 is shown.

Figure 5

Overview of the 16 aspect annotations information for human GPX4 in the iPCD. The detailed processing for each database is presented in Supplementary Methods, respectively.