Bioinformatic Analyses of Canonical Pathways of TSPOAP1 and its Roles in Human Diseases

Sharad Kumar Suthar,Mohammad Maqusood Alam,Jihye Lee,Alex Joseph,Sang-Yoon Lee,Jitender Monga

doi:10.3389/fmolb.2021.667947

Abstract

TSPO-associated protein 1 (TSPOAP1) is a cytoplasmic protein and is closely associated with its mitochondrial transmembrane protein partner translocator protein (TSPO). To decipher the canonical signalling pathways of TSPOAP1, its role in human diseases and disorders, and relationship with TSPO; expression analyses of TSPOAP1- and TSPO-associated human genes were performed by Qiagen Ingenuity Pathway Analysis (IPA). In the expression analysis, necroptosis and sirtuin signalling pathways, mitochondrial dysfunction, and inflammasome were the top canonical pathways for both TSPOAP1 and TSPO, confirming the close relationship between these two proteins. A distribution analysis of common proteins in all the canonical pathways predicted for TSPOAP1 revealed that tumor necrosis factor receptor 1 (TNFR1), vascular cell adhesion molecule 1 (VCAM1), cyclic AMP response element-binding protein 1 (CREB1), T-cell receptor (TCR), nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain containing 3 (NLRP3), DNA-dependent protein kinase (DNA-PK or PRKDC), and mitochondrial permeability transition pore (mPTP) were the major interaction partners of TSPOAP1, highlighting the role of TSPOAP1 in inflammation, particularly neuroinflammation. An analysis of the overlap between TSPO and TSPOAP1 Homo sapiens genes and top-ranked canonical pathways indicated that TSPO and TSPOAP1 interact via voltage-dependent anion-selective channels (VDAC1/2/3). A heat map analysis indicated that TSPOAP1 has critical roles in inflammatory, neuroinflammatory, psychiatric, and metabolic diseases and disorders, and cancer. Taken together, this information improves our understanding of the mechanism of action and biological functions of TSPOAP1 as well as its relationship with TSPO; furthermore, these results could provide new directions for in-depth functional studies of TSPOAP1 aimed at unmasking its detailed functions.

Highlights

translocator protein (TSPO) is an 18-kDa transmembrane protein of 169 residues predominantly localized in the outer mitochondrial membrane (Delavoie et al, 2003; Iacobazzi et al, 2017) (Figure 1A)
The canonical pathway analysis of Homo sapiens genes associated with TSPO-associated protein 1 (TSPOAP1) (Supplementary Table S1) and TSPO (Supplementary Table S2) identified the necroptosis, sirtuin signalling, mitochondrial dysfunction, and inflammasome pathways as the major signalling pathways (Figure 2A and Supplementary Figures S1–S8)
All the canonical pathways predicted by Ingenuity Pathway Analysis (IPA) for TSPOAP1 and TSPO are summarized in Table 1 and Supplementary Table S4, respectively, and in Supplementary Figure S1

Summary

Introduction

TSPO is an 18-kDa transmembrane protein of 169 residues predominantly localized in the outer mitochondrial membrane (Delavoie et al, 2003; Iacobazzi et al, 2017) (Figure 1A). It was first discovered in 1977 in a diazepam-binding site in the kidney and named peripheral-type benzodiazepine receptor (PBR) (Braestrup and Squires 1977). Other functions of TSPO are the formation of mitochondrial permeability transition pore (mPTP) in conjunction with VDAC in the outer mitochondrial membrane, adenine nucleotide transporter (ANT) in the inner mitochondrial membrane, and cyclophilin D (Veenman et al, 2018; Dimitrova-Shumkovska et al, 2020). The increased level of TSPO has been observed in neurodegenerative diseases and disorders (Rupprecht et al, 2010; Alam et al, 2017), brain injury (Papadopoulos and Lecanu 2009), and cancer (Decaudin et al, 2002; Li et al, 2007), while the dysregulation of TSPO has been detected in obesity (Kim et al, 2020) and diabetes (Giatti et al, 2009; Ilkan and Akar 2018)

Methods

Results

Conclusion