8.A.183. The RelA-associated Inhibitor (RAI) Family
RAI (Q9UKV5) is a regulator that plays a central role in the regulation of apoptosis and transcription via its interaction with NF-kappa-B and p53/TP53 proteins in humans. It blocks transcription of HIV-1 virus by inhibiting the action of both NF-kappa-B and SP1. It also inhibits p53/TP53 function, possibly by preventing the association between p53/TP53 and ASPP1 or ASPP2, and therefore suppressing the subsequent activation of apoptosis (Bergamaschi et al. 2003). Other designations include: PPP1R13L, iASPP and NKIP1. iASPP suppresses Gp78-mediated TMCO1 degradation to maintain Ca2+ homeostasis and control tumor growth and drug resistance (Zheng et al. 2022).
Ca2+ release from the endoplasmic reticulum (ER) is an essential event in the modulation of Ca2+ homeostasis, which is coordinated by multiple biological processes, ranging from cell proliferation to apoptosis. Deregulated Ca2+ homeostasis is linked with various cancer hallmarks. Zheng et al. 2022 demonstrated that a reported Ca2+-channel protein TMCO1 (transmembrane and coiled-coil domains 1) (TC# 1.A.106.1.1) is overexpressed in colon cancer tissues at protein levels but not at messenger RNA levels. TMCO1 is a substrate of ER-associated degradation E3 ligase Gp78. Intriguingly, Gp78-mediated TMCO1 degradation at K186 is under the control of the iASPP (inhibitor of apoptosis-stimulating protein of p53) oncogene. Mechanistically, iASPP robustly reduces ER Ca2+ stores, mainly by competitively binding with Gp78 and interfering with Gp78-mediated TMCO1 degradation. A positive correlation between the iASPP and TMCO1 proteins has been validated in human colon tissues. Inhibition of iASPP-TMCO1 axis promotes cytosolic Ca2+ overload-induced apoptotic cell death and reducing tumor growth both in vitro and in vivo (Zheng et al. 2022).
References:
The RelA-associated inhibitor, PPP1R13L, AMFR, RNF45. It is an inhibitor of the ASPP protein, iASPP, also called the NFkB-interacting protein 1 (Bergamaschi et al. 2003). See also the family description and Zheng et al. 2022. It is an E3 ubiquitin-protein ligase, AMFR, of 643 aas and 6 - 8 TMSs in the first (N-terminal) half of the protein. The second (C-terminal) half is hydrophilic. This E3 ubiquitin-protein ligase mediates the polyubiquitination of lysine and cysteine residues in target proteins, such as CD3D, CYP3A4, CFTR, INSIG1, SOAT2/ACAT2 and APOB for proteasomal degradation (Shimizu et al. 1999, Liu et al. 2014, Wang et al. 2017). Homologs of AMFR can be found in the ER-RT family (TC# 3.A.16), the PPI family (TC# 3.A.20) and the Rcf family (8.A.112).
PPP1R13L of Homo sapiens
E3 ubiquitin protein ligase, RIN2 isoform X3, of 505 aas and 6 TMSs.
RIN2 of Arachis hypogaea (peanut)
E3 ubiquitin-protein ligase, synoviolin, Syvn1, of 621 aas and 6 TMSs.
Synoviolin of Anguilla anguilla (European eel)
E3 ubiquitin-protein ligase, Hrd1, of 853 aas and 6 TMSs. The N-terminal transmembrane domain resembles that of Q6NPT7 (TC# 3.A.16.1.5) while the C-terminal domain is rich in serine and proline, resembling S7UI33 (TC# 1.A.17.2.5)
Hrd1 of Ceratobasidium sp. 395
E3 ubiquitin ligase RIN2-like protein of 402 aas and 6 - 8 TMSs.
RIN2 of Micractinium conductrix
ERAD-associated E3 ubiquitin-protein ligase, HRD1, of 458 aas and 6 TMSs.
HRD1 of Plasmodium falciparum
Lipid droplet-regulated VLDL assembly factor, AUP1 of 410 aas and possibly as many as 4 TMSs at residue positions 20 - 60 ( 2 TMSs) + 1 at residue 200 + 1 at about residue 340. It plays a role in the translocation of terminally misfolded proteins from the endoplasmic reticulum (ER) lumen to the cytoplasm and their degradation by a proteasome. It also plays a role in lipid droplet formation and induces lipid droplet clustering (Klemm et al. 2011). It also regulates the ER-associated degradation and polyubiquitination of NKCC2 (Frachon et al. 2024).
AUP1 of Homo sapiens