NRADD, a novel membrane protein with a death domain involved in mediating apoptosis in response to ER stress

Abstract

NRADD (neurotrophin receptor alike death domain protein) is a novel protein with transmembrane and cytoplasmic regions highly homologous to death receptors, particularly p75 NTR . However, the short N-terminal domain is unique. Expression of NRADD induced apoptosis in a number of cell lines. The apoptotic mechanism involved the activation of caspase-8 and execution of apoptosis without requiring mitochondrial components. The activation of this death receptor-like mechanism required the N-terminal domain, which is Nglycosylated and needed for subcellular targeting. Deletion of the N-terminal domain produced a dominant-negative form of NRADD that protected neurons and Schwann cells from a variety of endoplasmic reticulum (ER) stressors. NRADD may therefore be a necessary component for generating an ERinduced proapoptotic signal.

Caspase-12: an overview

“…Mus musculus (m), Homo sapiens (h), *the catalytic part of the hypothetical fulllength human pseudo-caspase-12 was used tunicamycin and brefeldin A) in ST14A and Schwann cells. 12 Taken together, the results reported for Bap31, NRADD and caspase-8 suggest that caspase-8 may be another ERstress-associated protease. 12 In support of an important role for caspase-8 in ER stress is the observation that caspase-8 deficiency significantly delays the onset of tunicamycininduced DNA fragmentation, while caspase-12 deficiency hardly has any effect on both DNA fragmentation and caspase activation.…”

“…12 Taken together, the results reported for Bap31, NRADD and caspase-8 suggest that caspase-8 may be another ERstress-associated protease. 12 In support of an important role for caspase-8 in ER stress is the observation that caspase-8 deficiency significantly delays the onset of tunicamycininduced DNA fragmentation, while caspase-12 deficiency hardly has any effect on both DNA fragmentation and caspase activation. 18 Nevertheless, the exact roles of these proapoptotic factors during ER-stress-induced apoptosis need further investigation.…”

“…On the one hand, it has been proposed that caspase-12 is not processed and activated following serum deprivation in rat PC12 pheochromocytoma cells, in etoposide-treated ST14A cells, a rat striatum-derived neuronal progenitor cell line, 11,12 or during TNF-and FasLinduced apoptosis in rat W4 fibrosarcoma cells. 10 Serum withdrawal and etoposide treatment are well-known inducers of the intrinsic mitochondrial apoptotic pathway, while TNFand FasL-induced apoptosis are examples of the well-studied extrinsic death receptor pathway.…”

“…15,17 Scotin and NRADD are two additional ER-residing proapoptotic molecules that have recently been discovered. 12,17 Scotin has been implicated in p53-mediated apoptosis. 17 In ST14A cells, CrmA and the vFLIP proteins E8 and MC159 inhibit NRADD-induced apoptosis.…”

Plasminogen activator inhibitor 1: Mechanisms of its synergistic regulation by growth factors

“…These results support observations made by others that AS-ODNs targeted to the region of the translational start site are likely to be effective in suppressing translational initiation (Higgins, Perez et al 1993;Reed 1997;Dias and Stein 2002). However, a BLAST search of the AS-ODN11 sequence revealed that, as well as being complementary to position 11-27 of Lcn2, it is also complementary to position 702-719 of the mRNA that encodes Nradd (Neurotrophin receptor associated death domain, GeneID: #67169, NM_026012), a death domain protein (Wang, Shao et al 2003;Gowrishankar, Zeidler et al 2004). Thus, the effect of AS-ODN11 on Lcn2 expression could be an indirect consequence of the inhibition of Nradd production due to a primary antisense effect on the level of Nradd mRNA.…”