Structural Features and Physiological Associations of Human 14-3-3ζ Pseudogenes.

There are about 14,000 pseudogenes that are mutated or truncated sequences resembling functional parent genes. About two-thirds of pseudogenes are processed, while others are duplicated. Although initially thought dead, emerging studies indicate they have functional and regulatory roles. We study 14-3-3ζ, an adaptor protein that regulates cytokine signaling and inflammatory diseases, including rheumatoid arthritis, cancer, and neurological disorders. To understand how 14-3-3ζ (gene symbol YWHAZ) performs diverse functions, we examined the human genome and identified nine YWHAZ pseudogenes spread across many chromosomes. Unlike the 32 kb exon-to-exon sequence in YWHAZ, all pseudogenes are much shorter and lack introns. Out of six, four YWHAZ exons are highly conserved, but the untranslated region (UTR) shows significant diversity. The putative amino acid sequence of pseudogenes is 78-97% homologous, resulting in striking structural similarities with the parent protein. The OMIM and Decipher database searches revealed chromosomal loci containing pseudogenes are associated with human diseases that overlap with the parent gene. To the best of our knowledge, this is the first report on pseudogenes of the 14-3-3 family protein and their implications for human health. This bioinformatics-based study introduces a new insight into the complexity of 14-3-3ζ's functions in biology.

Hemopexin accumulates in kidneys and worsens acute kidney injury by causing hemoglobin deposition and exacerbation of iron toxicity in proximal tubules.

Hemopexin, a heme scavenging protein, accumulates in the kidneys during acute kidney injury (AKI). However, the function of this accumulated hemopexin in the kidney is unclear. In both the cisplatin-induced and the unilateral kidney ischemia-reperfusion injury models of AKI, we found accumulation of hemoglobin and hemopexin in the kidneys localized to the proximal tubules. Next, hemopexin wild-type and knockout mice were compared in both AKI models and hemopexin wild type mice had significantly worse kidney injury. Furthermore, there was increased kidney expression of kidney injury molecule-1 (a biomarker of AKI) and heme oxygenase-1 (an indicator of oxidative stress) in hemopexin wild type compared with knockout mice in both models of AKI. Next, the interaction of hemopexin and hemoglobin in vitro was investigated using cultured proximal tubular cells. Co-incubation of hemopexin with hemoglobin resulted in hemoglobin deposition and exaggerated hemoglobin-induced injury. Deferoxamine, an iron chelator, and ferrostatin-1, a ferroptosis inhibitor, inhibited this deleterious effect of hemoglobin and hemopexin in proximal tubular cells, implicating iron toxicity in the mechanism of hemopexin mediated injury. Furthermore, the protective effect of deferoxamine in cisplatin-induced AKI was apparent in hemopexin wild type, but not in hemopexin knockout mice, further implicating hemopexin as a mediator of iron toxicity in AKI. Thus, our findings demonstrate that hemopexin accumulates in the kidneys and worsens kidney injury in AKI by increasing hemoglobin deposition on proximal tubular cells to exaggerate hemoglobin-induced cell injury.