Ubiquitin Ligase RNF5


RNF5 (RING finger domain E3 ligase), also known as RMA1, is an membrane anchored (ER and/or mitochondria) E3 ubiquitin ligase. Anchored to the ER membrane via a single transmembrane-spanning domain located within the C-terminal region, RNF5 also consists of a RING domain, and a formin-like homology domain.

RNF5 emerges as a regulator of ER Associated Degradation (ERAD), and as part of the greater ER stress response that specializes in the degradation of misfolded proteins. RNF5 contributes to control of autophagy, glutamine metabolism as well as in cytoskeletal organization. The following summarizes key observations for RNF5. 

 By mediating ubiquitination of paxillin, RNF5 affects cell motility.

RNF5 is deregulated in Inclusion Body Myocytis (IBM) - a muscle disorder. Transgenic RNF5 mice exhibit phenotypes that resemble IBM and samples from IBM patients exhibit deregulation of RNF5 expression.

RNF5 regulates a 7 transmembrane protein, JAMP, which anchors proteasomes to the ER. This occurs prior to- and after- ER stress response, thereby confines ERAD and proteasome assembly at the ER domain, to the actual ER stress response.

RNF5 negatively regulates basal levels of autophagy by mediating ubiquitination and degradation of ATG4B, thereby limiting basal autophagy under conditions when it is not required. RNF5 KO mice exhibit resistance to GAS infection, through improved autophagy of the pathogen in their macrophages. 

RNF5 expression is elevated in breast cancer samples (RNA and protein) and inhibition of RNF5 sensitizes BCa cells to chemotherapy-induced death. 

RNF5 control of glutamine carrier proteins (SLC1A5 and SLC38A2) was found to result in their degradation in breast cancer cells that are subjected to ER stress induced by chemotherapies like Paclitaxel. As a result, breast cancer cells are more sensitive to these therapies. Yet, 50% of breast cancer up regulates SLC1A5 and SLC38A2, rendering them insensitive to such therapies. Our findings establish mechanism for control of glutamine metabolism and the significan to breast cancer response and stratification to select therapies.

         from left: Yongmei Feng, Hyungsoo Kim, Hiro Tamiya, Yan Li


OPEN QUESTIONS

Characterization of RNF5 in immune checkpoint control 

Understanding of RNF5 function in glutamine metabolism in breast cancer and melanoma.

 the link between glutamine metabolism and susceptibility to taxane therapy in breast cancer, prompted the analogy with the tale on the hare and the turtle, where the racing rabbit is driven by greater amount of glutamine, which also promotes the developement of the tumor and its poor response to therapy.


Supported by:

Hervey Family Non-Endowment Fund at the San Diego Foundation

© Ronai Lab 2016