RNF13: a novel RING-type ubiquitin ligase over-expressed in pancreatic cancer

Background:The mechanistic role of MTA1 in tumor aggressiveness is yet to be deciphered. Results: RNF144A is a direct target of transcriptional repression by MTA1 and inhibits migration and invasion. Conclusion: Transcriptional repression of RNF144A by MTA1 confers a migratory and invasive phenotype of cancer cells. Significance: This study provides novel mechanistic insights into regulation of tumor progression by MTA1.

Section: Discussionmentioning

confidence: 99%

Metastasis-associated Protein 1 Drives Tumor Cell Migration and Invasion through Transcriptional Repression of RING Finger Protein 144A

Marzook

Nair

et al. 2012

“…Among some members in the family, the RING domains have been shown to possess ubiquitin E3 ligase activity and are involved in diverse cellular processes including cancer metastasis (22). However, RNF13 has only been studied quite recently, and its role as an E3 ligase to promote the degradation of downstream substrate has not yet been well characterized (22, 26 -28).…”

Section: Discussionmentioning

confidence: 99%

RNF13, a RING Finger Protein, Mediates Endoplasmic Reticulum Stress-induced Apoptosis through the Inositol-requiring Enzyme (IRE1α)/c-Jun NH2-terminal Kinase Pathway

Arshad

et al. 2013

Background: Endoplasmic reticulum (ER) stress-induced apoptosis is mediated by IRE1␣-JNK pathway. Results: Knockdown or inactivation of RNF13 results in resistance to ER stress-induced apoptosis, whereas RNF13 overexpression induces JNK activation and apoptosis. RNF13 interacts with IRE1␣ to promote JNK activation and apoptosis. Conclusion: RNF13 mediates ER stress-induced apoptosis through IRE1␣/JNK pathway. Significance: RNF13 is a novel regulator of ER stress-induced apoptosis.

“…Although the importance of regulated degradation of ER resident proteins is firmly established, only a small number of RING finger-containing ubiquitin ligases are known to be involved in such processes to date, namely SYVN1/hHrd1 (6,12), AMFR/gp78 (13), TEB4/MARCH6 (14), RNF5/Rma1 (15), RNF77/TRIM13 (16), and RNF13 (17). Given the importance of protein metabolism and degradation in the ER and the vast number of ubiquitin ligases encoded in the human genome, we asked whether other ubiquitin ligases are involved in the regulation of ER-related degradation processes.…”

mentioning

confidence: 99%

A Systematic Search for Endoplasmic Reticulum (ER) Membrane-associated RING Finger Proteins Identifies Nixin/ZNRF4 as a Regulator of Calnexin Stability and ER Homeostasis

Neutzner

Benischke

et al. 2011

To identify novel regulators of endoplasmic reticulum (ER)-linked protein degradation and ER function, we determined the entire inventory of membrane-spanning RING finger E3 ubiquitin ligases localized to the ER. We identified 24 ER membraneanchored ubiquitin ligases and found Nixin/ZNRF4 to be central for the regulation of calnexin turnover. Ectopic expression of wild type Nixin induced a dramatic down-regulation of the ER-localized chaperone calnexin that was prevented by inactivation of the Nixin RING domain. Importantly, Nixin physically interacts with calnexin in a glycosylation-independent manner, induces calnexin ubiquitination, and p97-dependent degradation, indicating an ER-associated degradation-like mechanism of calnexin turnover.The endoplasmic reticulum (ER) 3 is a major cellular site for production, folding, quality control, and distribution of proteins. Many regulatory mechanisms are in place to keep these processes in balance and therefore to ensure cellular fitness and survival, with ubiquitin-dependent protein degradation playing an important part (1). One major challenge the ER faces is an overload with unfolded or folding proteins. An excess of folding proteins in the ER triggers a cellular response called the unfolded protein response (UPR) (2, 3). UPR entails lowering of the protein load by the attenuation of protein translation and the up-regulation of chaperones thereby increasing the protein folding capacity of the cells. If the capacity of UPR is exceeded, the cell utilizes ER-associated degradation (ERAD), a system for the recognition of terminally misfolded proteins and their disposal (4). Misfolded proteins destined for ERAD are ubiquitinated by the RING domain containing ubiquitin ligases (5), Hrd1 (6), and Doa1 (7, 8), retrotranslocated across the ER membrane into the cytosol by the AAA-ATPase p97 (9), and then degraded by the 26 S proteasome.Upon entry into the ER, most nascent polypeptides are recognized by glycosidases and modified on specific asparagine residues (Asn-Xaa-(Thr/Ser)) with the N-glycan GlcNAc 2 Man 9 Gluc 3 (10). Core glycosylation of nascent polypeptides decreases their overall hydrophobicity. Trimming of the terminal two glucose residues by glucosidase I allows for binding of the lectins/chaperones calreticulin and calnexin thereby facilitating the proper folding of the newly synthesized protein (10,11).Although the importance of regulated degradation of ER resident proteins is firmly established, only a small number of RING finger-containing ubiquitin ligases are known to be involved in such processes to date, namely SYVN1/hHrd1 (6, 12), AMFR/gp78 (13), TEB4/MARCH6 (14), RNF5/Rma1 (15), RNF77/TRIM13 (16), and RNF13 (17). Given the importance of protein metabolism and degradation in the ER and the vast number of ubiquitin ligases encoded in the human genome, we asked whether other ubiquitin ligases are involved in the regulation of ER-related degradation processes.Based on the assumption that the ER lumen is devoid of E1 and E2 ubiquitination activity and on the...