Overview of Human HtrA Family Proteases and Their Distinctive Physiological Roles and Unique Involvement in Diseases, Especially Cancer and Pregnancy Complications.

Yao Wang,Guiying Nie

doi:10.3390/ijms221910756

Abstract

The mammalian high temperature requirement A (HtrA) proteins are a family of evolutionarily conserved serine proteases, consisting of four homologs (HtrA1-4) that are involved in many cellular processes such as growth, unfolded protein stress response and programmed cell death. In humans, while HtrA1, 2 and 3 are widely expressed in multiple tissues with variable levels, HtrA4 expression is largely restricted to the placenta with the protein released into maternal circulation during pregnancy. This limited expression sets HtrA4 apart from the rest of the family. All four HtrAs are active proteases, and their specific cellular and physiological roles depend on tissue type. The dysregulation of HtrAs has been implicated in many human diseases such as cancer, arthritis, neurogenerative ailments and reproductive disorders. This review first discusses HtrAs broadly and then focuses on the current knowledge of key molecular characteristics of individual human HtrAs, their similarities and differences and their reported physiological functions. HtrAs in other species are also briefly mentioned in the context of understanding the human HtrAs. It then reviews the distinctive involvement of each HtrA in various human diseases, especially cancer and pregnancy complications. It is noteworthy that HtrA4 expression has not yet been reported in any primary tumour samples, suggesting an unlikely involvement of this HtrA in cancer. Collectively, we accentuate that a better understanding of tissue-specific regulation and distinctive physiological and pathological roles of each HtrA will improve our knowledge of many processes that are critical for human health.

Highlights

The high temperature requirement A (HtrA) proteins are a family of evolutionarily conserved serine proteases that are found in a large number of organisms ranging from prokaryotes, yeasts, and fungi to plants, birds, fish, and mammals [1,2]
In neuronal PC12 cells, HtrA1 mRNA and activity are upregulated in response to tau, and in patient brain samples, the extent of tau aggregates inversely correlates to the level of HTRA1 expression; these results suggest an important role for HtrA1 in regulating protein quality control for neurological functions [57]
It is reported that both HtrA3 isoforms can bind to and cleave the X-linked inhibitor of apoptosis protein (XIAP) to significantly reduce its cellular levels in lung cancer cells when treated with etoposide, indicating a possible mechanism of HtrA3 action in promoting cancer cell death following chemotherapy [72]

Summary

Introduction

The high temperature requirement A (HtrA) proteins are a family of evolutionarily conserved serine proteases that are found in a large number of organisms ranging from prokaryotes, yeasts, and fungi to plants, birds, fish, and mammals [1,2]. All four human HtrAs contain the signature motif of a HtrA, a chymotrypsin-like serine protease domain and a C-terminal PDZ domain (Figure 1) [25]. It is noteworthy that the IGFBP-Kazal tandem is exclusively found in these HtrAs and another three mammalian proteins (Mac, Kazal D1, IGFBPL1) [29] These differences suggest that HtrA1, 3 and 4 may have evolved to fulfil more mammalian specific cellular and physiological functions, whereas HtrA2 may have retained certain features of the ancient HtrAs. studies suggest that all four human HtrAs are active proteases and all form a trimeric or higher oligomeric assembly as prokaryotic HtrAs (Figure 1B), the regulation of oligomerisation and protease activity of HtrA2 resembles that of prokaryotic HtrAs, whereas that of HtrA1, 3 and 4 is distinctly different [16]. A structural and functional analysis has found no evidence that these modules in HtrA1 retain their prototypic functions—the IGFBP region neither binds to IGFs nor behaves like an IGFBP, and the Kazal-like segment does not affect the HtrA1 proteolytic activity as would be expected of a protease inhibitor [29]

Tissue Distribution

Key Molecular Characteristics

Conclusions