The HtrA family of serine proteases

Pallen, Mark J.; Wren, Brendan W.

doi:10.1046/j.1365-2958.1997.5601928.x

Cited by 367 publications

(436 citation statements)

References 58 publications

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“…Omi is a member of the family of heat shock endoproteases defined by bacterial HtrA (Pallen and Wren, 1997;Faccio et al, 2000;Gray et al, 2000). Like the ancestral protease HtrA, Omi harbors a PDZ domain in the C-terminal one-third of its primary structure.…”

Section: Discussionmentioning

confidence: 99%

Serine protease Omi/HtrA2 targets WARTS kinase to control cell proliferation

et al. 2006

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The serine protease Omi/HtrA2 was initially regarded as a proapoptotic molecule that proteolyses several proteins to induce cell death. Recent studies, however, indicate that loss of Omi protease activity increases susceptibility to stress-induced cell death. These complicated findings suggest that the protease activity of Omi is involved not only in apoptosis but also in cellular homeostasis. However, the targets which Omi uses to mediate this novel process are unknown. Previously, we showed that WARTS (WTS)/large tumor-suppressor 1 mitotic kinase interacts with the protein/discs-large protein/zonula (PDZ) domain of Omi and promotes its protease activity. We now report that WTS is a substrate for Omi protease activity, thus it is not only a regulator but also a downstream target of this protease. Interaction with Omi PDZ domain is required for WTS to be proteolysed. When caspase-9-deficient mouse embryonic fibroblasts (MEFs) were treated with staurosporine, WTS was proteolysed by activated endogenous Omi without induction of cell death. Therefore, protease activity of Omi and proteolysis of WTS are not necessarily required for cell death. We found that depletion of Omi from HeLa cells results in accelerated cell proliferation despite no significant change in the duration of mitosis. The depletion of WTS showed the same effect on S phase progression. Therefore, WTS proteolytic fragment(s) generated by Omi may act as an inhibitor of G1/S progression. Our data reveal a role for Omi-mediated processing of WTS in negative regulation of cell cycle progression at interphase, suggesting a novel function of Omi other than apoptosis.

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Section: Discussionmentioning

confidence: 99%

Serine protease Omi/HtrA2 targets WARTS kinase to control cell proliferation

et al. 2006

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“…HtrA was originally identified as a heat-shock-induced serine protease in Escherichia coli that degrades misfolded proteins. 1 HtrA proteases contain one or two C-terminal PDZ domains that activate the trypsin-like protease domain once they recognize misfolded or damaged proteins. 2 The mammalian HtrA2 protease, Omi, is much better known than other HtrA family members for its proapoptotic activity.…”

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confidence: 99%

Omi/HtrA2 is a positive regulator of autophagy that facilitates the degradation of mutant proteins involved in neurodegenerative diseases

Wang

et al. 2010

Cell Death Differ

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Omi, also known as high temperature requirement factor A2 (HtrA2), is a serine protease that was originally identified as a proapoptotic protein. Like Smac/Diablo, it antagonizes inhibitor of apoptosis proteins when released into the cytosol on apoptotic stimulation. Loss of its protease activity in mnd2 (motor neuron degeneration 2) mice is associated with neurodegeneration. However, the detailed mechanisms by which Omi regulates the pathogenesis of neurodegenerative disease remain largely unknown. We report here that Omi participates in the pivotal cellular degradation process known as autophagy. It activates autophagy through digestion of Hax-1, a Bcl-2 family-related protein that represses autophagy in a Beclin-1 (mammalian homologue of yeast ATG6)-dependent pathway. Moreover, Omi-induced autophagy facilitates the degradation of neurodegenerative proteins such as pathogenic A53T a-synuclein and truncated polyglutamine-expanded huntingtin, as well as the endogenous autophagy substrate p62. Knockdown of Omi decreases the basal level of autophagy and increases the level of the above target proteins. Furthermore, S276C Omi, the protease-defective mutant found in mnd2 mice, fails to regulate autophagy. Increased autophagy substrates and the formation of aggregate structures are observed in the brains of mnd2 mice. These results identify Omi as a novel regulator of autophagy and suggest that Omi might be important in the cellular quality control of proteins involved in neurodegenerative diseases.

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“…1,7 The bacterial serine-protease HtrA, also known as DegP, is a heat shock-induced envelope-associated serine protease. 8 Its main role is to recognize and degrade misfolded proteins in the periplasm, combining a dual activity of chaperone and protease. 9 Four human homologues of HtrA have been identified and named respectively human HtrA1 (PRSS11 or L56), 10 HtrA2 (Omi), 11 HtrA3 (PRSP) and HtrA4.…”

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confidence: 99%

HtrA1-dependent proteolysis of TGF-β controls both neuronal maturation and developmental survival

et al. 2008

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Transforming growth factor-b (TGF-b) signalling controls a number of cerebral functions and dysfunctions including synaptogenesis, amyloid-b accumulation, apoptosis and excitotoxicity. Using cultured cortical neurons prepared from either wild type or transgenic mice overexpressing a TGF-b-responsive luciferase reporter gene (SBE-Luc), we demonstrated a progressive loss of TGF-b signalling during neuronal maturation and survival. Moreover, we showed that neurons exhibit increasing amounts of the serine protease HtrA1 (high temperature responsive antigen 1) and corresponding cleavage products during both in vitro neuronal maturation and brain development. In parallel of its ability to promote degradation of TGF-b1, we demonstrated that blockage of the proteolytic activity of HtrA1 leads to a restoration of TGF-b signalling, subsequent overexpression of the serpin type -1 plasminogen activator inhibitor (PAI-1) and neuronal death. Altogether, we propose that the balance between HtrA1 and TGF-b could be one of the critical events controlling both neuronal maturation and developmental survival.

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The HtrA family of serine proteases

Cited by 367 publications

References 58 publications

Serine protease Omi/HtrA2 targets WARTS kinase to control cell proliferation

Serine protease Omi/HtrA2 targets WARTS kinase to control cell proliferation

Omi/HtrA2 is a positive regulator of autophagy that facilitates the degradation of mutant proteins involved in neurodegenerative diseases

HtrA1-dependent proteolysis of TGF-β controls both neuronal maturation and developmental survival

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