The zinc finger protein NRIF interacts with the neurotrophin receptor p75NTR and participates in programmed cell death

Abstract

contributed equally to this work NRIF (neurotrophin receptor interacting factor) is a ubiquitously expressed zinc finger protein of the Krü ppel family which interacts with the neurotrophin receptor p75 NTR . The interaction was first detected in yeast and then biochemically confirmed using recombinant GST-NRIF fusions and p75 NTR expressed by eukaryotic cells. Transgenic mice carrying a deletion in the exon encoding the p75 NTRbinding domain of NRIF display a phenotype which is strongly dependent upon genetic background. While at the F 2 generation there is only limited (20%) embryonic lethality, in a congenic BL6 strain nrif -/-mice cannot survive beyond E12, but are viable and healthy to adulthood in the Sv129 background. The involvement of NRIF in p75 NTR /NGF-mediated developmental cell death was examined in the mouse embryonic neural retina. Disruption of the nrif gene leads to a reduction in cell death which is quantitatively indistinguishable from that observed in p75 NTR-/-and ngf -/-mice. These results indicate that NRIF is an intracellular p75 NTRbinding protein transducing cell death signals during development.

Neurotrophins: key regulators of cell fate and cell shape in the vertebrate nervous system

“…3), many of them as a result of yeast two-hybrid screens. P75 interactors involved in transducing cell death include a ubiquitously expressed zinc finger protein designated NRIF (neuro-trophin receptor-interacting factor; Casademunt et al 1999). The retinae of nrif−/− mice show reduced cell death, and this reduction is quantitatively similar to that seen in p75−/− and ngf−/− mice.…”

Receptors that mediate cellular dependence

“…94 Other potential death-mediating p75 NTR interactors include NRAGE 49 and NRIF. 95 Another proapoptotic transmembrane protein has been identified that has a death domain very similar to that of p75 NTR , and this protein interacts with p75 NTR . 96 The protein, dubbed p75 NTR -like apoptosis-inducing death domain protein (PLAIDD) and also referred to as neurotrophin receptor homologue 2 (NRH2), 97 displays a type II death domain (which is structurally slightly different from the type I death domains displayed by death receptors such as Fas and TNFR I) that is closely related to the type II death domain of p75 NTR , with 42% identity.…”

Activation of Rac GTPase by p75 Is Necessary for c-junN-Terminal Kinase-Mediated Apoptosis

“…The mechanism by which p75 activates JNK is still unknown. Although nine different molecules are known to interact with p75 to date, none of them has been linked to the JNK pathway (Casademunt et al, 1999;Chittka and Chao, 1999;Irie et al, 1999;Khursigara et al, 1999;Yamashita et al, 1999;Ye et al, 1999;Salehi et al, 2000). We therefore sought to find an upstream regulator that may be most proximal to the receptor.…”