THAP5 is a human cardiac-specific inhibitor of cell cycle that is cleaved by the proapoptotic Omi/HtrA2 protease during cell death

Abstract

Balakrishnan MP, Cilenti L, Mashak Z, Popat P, Alnemri ES, Zervos AS. THAP5 is a human cardiac-specific inhibitor of cell cycle that is cleaved by the proapoptotic Omi/HtrA2 protease during cell death. Am J Physiol Heart Circ Physiol 297: H643-H653, 2009. First published June 5, 2009 doi:10.1152/ajpheart.00234.2009.-Omi/ HtrA2 is a mitochondrial serine protease that has a dual function: while confined in the mitochondria, it promotes cell survival, but when released into the cytoplasm, it participates in caspase-dependent as well as caspase-independent cell death. To investigate the mechanism of Omi/HtrA2's function, we set out to isolate and characterize novel substrates for this protease. We have identified Thanatosassociated protein 5 (THAP5) as a specific interactor and substrate of Omi/HtrA2 in cells undergoing apoptosis. This protein is an uncharacterized member of the THAP family of proteins. THAP5 has a unique pattern of expression and is found predominantly in the human heart, although a very low expression is also seen in the human brain and muscle. THAP5 protein is localized in the nucleus and, when ectopically expressed, induces cell cycle arrest. During apoptosis, THAP5 protein is degraded, and this process can be blocked using a specific Omi/HtrA2 inhibitor, leading to reduced cell death. In patients with coronary artery disease, THAP5 protein levels substantially decrease in the myocardial infarction area, suggesting a potential role of this protein in human heart disease. This work identifies human THAP5 as a cardiac-specific nuclear protein that controls cell cycle progression. Furthermore, during apoptosis, THAP5 is cleaved and removed by the proapoptotic Omi/HtrA2 protease. Taken together, we provide evidence to support that THAP5 and its regulation by Omi/ HtrA2 provide a new link between cell cycle control and apoptosis in cardiomyocytes.Omi/HtrA2; Thanatos-associated protein 5; coronary artery disease; apoptosis OMI/HTRA2 IS A MITOCHONDRIAL serine protease that has an essential role in both mitochondrial homeostasis, as well as cell death (49). Most of the studies on Omi/HtrA2 have substantially contributed to our understanding of the mechanism of its proapoptotic function. On the contrary, very little is known about its normal function within the mitochondria. Upon induction of apoptosis, Omi/HtrA2 is released to the cytoplasm, where it participates in caspase-dependent and caspase-independent cell death (21,34,45,48,50). The mechanism of its proapoptotic activity involves degradation of specific substrates that include mitochondrial protein HS1-associated protein X-1, cytoplasmic proteins X-chromosome-linked inhibitor, PEA/PED, and Apollon/Bruce (10,41,44,47,51), as well as nuclear factors WARTS, and p73 (28,29,31,33). The protease activity of Omi/HtrA2 is always necessary and essential for its proapoptotic function. We have used the yeast two-hybrid system to isolate and characterize new Omi/HtrA2 interacting proteins (10). These interacting proteins could be new substrates of Omi/HtrA...

Acute administration of ucf-101 ameliorates the locomotor impairments induced by a traumatic spinal cord injury

“…As shown before, ucf-101 also activates key components of the adaptive cellular response to insults independently from its inhibitory activity on HtrA2/Omi (Balakrishnan et al, 2009;Hu et al, 2013;Li et al, 2009aLi et al, , 2009b.In particular, it promotes cell survival through the phosphorylation of both p44 and p42 MAPkinases (ERK1 and ERK2) in wild-type and HtrA2-knockout MEFs and neuro-2A cells (Klupsch and Downward, 2006). In agreement, we observed that ucf-101 treatment induces ERK phosphorylation in both the injured spinal cord and the Neuro2a cells, although ERK2 phosphorylation may also activate secondary injury events including glutamate excitotoxicity and contribute to neuronal death (Yu et al, 2010).…”

“…Ucf-101 is a cell-permeable reversible inhibitor of the pro-apoptotic protein HtrA2/OMI (Faccio et al, 2000;Gray et al, 2000) with cytoprotective effects both in vitro and in vivo (Bhuiyan and Fukunaga, 2008;Cilenti et al, 2003;Liu et al, 2005). Ucf-101 also inhibits the extrinsic apoptotic TNF and FasL signalling pathways (Bhuiyan and Fukunaga, 2008;Blink et al, 2004;Cilenti et al, 2003;Su et al, 2009;Trencia et al, 2004), and activates key components of the adaptive cellular response to insults (Balakrishnan et al, 2009;Hu et al, 2013;Li et al, 2009aLi et al, , 2009b) (see figure 1). Treatment with ucf-101 in rodent models of brain ischemia proved to be markedly cytoprotective, reducing the number of TUNEL-positive cells and the infarct size, and improving the functional recovery (Althaus et al, 2007;Su et al, 2009).…”

“…At higher concentrations, ucf-101 has additional cytoprotective properties due to its inhibitory activity on TNF (Blink et al, 2004) and FasL (Bhuiyan and Fukunaga, 2007;Su et al, 2009) signaling to the extrinsic pathway of apoptosis, as well as on the activation of key components of the adaptive cellular response to insults (vg. eIF2) and of prosurvival pathways such as p44/p46 (ERK1/2) (Balakrishnan et al, 2009;Hu et al, 2013;Klupsch and Downward, 2006;Li et al, 2009aLi et al, , 2009bTrencia et al, 2004) (see Fig. 1).…”

A Transcriptional Regulatory Role of the THAP11–HCF-1 Complex in Colon Cancer Cell Function

“…The majority of conserved THAP proteins also contain a coiled-coil protein interaction domain adjacent to a host cell factor 1 (HCF-1)-binding motif (HBM) (26). The tetrapeptide HBM (E/DHXY, where X is any amino acid) facilitates the interaction of THAP proteins and other DNA-binding factors with the Kelch domain of HCF-1, a transcriptional coregulator and cell proliferation factor associated with a variety of enzymatic and histone-modifying activities, including SIN3/HDAC histone deacetylase, SET1/MLL histone methyltransferase, and MOF histone acetyltransferase (11,22,23,26,30,39,42).Individual THAP proteins have been implicated in a diverse array of physiological processes, including cell proliferation, regulation of transcription, apoptosis, and maintenance of embryonic stem (ES) cell pluripotency (2,3,6,9,12,24,33,45). The DNA-and HCF-1-binding properties of THAP proteins naturally suggest that these proteins may regulate normal or disease-specific physiological processes in a DNA-and chromatin-dependent manner.…”

“…Individual THAP proteins have been implicated in a diverse array of physiological processes, including cell proliferation, regulation of transcription, apoptosis, and maintenance of embryonic stem (ES) cell pluripotency (2,3,6,9,12,24,33,45). The DNA-and HCF-1-binding properties of THAP proteins naturally suggest that these proteins may regulate normal or disease-specific physiological processes in a DNA-and chromatin-dependent manner.…”