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Ubiquitin Ligase RNF5
From left: Yongmei Feng, Hyungsoo Kim, Hiro Tamiya, Yan Li

RNF5 (RING finger domain E3 ligase), also known as RMA1, is a membrane-anchored (ER and/or mitochondria) E3 ubiquitin ligase. Anchored to the ER membrane via a single transmembrane, spanning the 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 (BCa) 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, BCa cells are more sensitive to these therapies. Yet, 50% of BCa up regulates SLC1A5 and SLC38A2, rendering them insensitive to such therapies. Our findings establish a mechanism for the control of glutamine metabolism and the significance to BCa response and stratification to select therapies.

RNF5 control of gut microbiome and immune checkpoint activity – ongoing studies led by Yan Li in collaboration with Ali Khateb and members of the labs at SBP and Technion identified an unexpected role of RNF5 in coordinated regulation of gut microbiota and anti-tumor immunity.

 

RNF5 control of intestinal inflammatory disorders – ongoing studies led by Yu Fujita in collaboration with Yan Li at SBP and with Ali Khateb at the Technion identified the importance of RNF5 in intestinal epithelial cell homeostasis and their interaction with the immune system.

 

RNF5 control of AML proliferation and viability – ongoing studies led by Ali Khateb at the Technion lab identify the importace of RNF5 in AML and the mechanism by which RNF5 alters AML cell viability and proliferation capacities.

OPEN QUESTIONS:

  • Characterization of RNF5 in immune checkpoint control.

  • Developing small molecule inhibitors for SLC1A5, RNF5 substrate.

  • Defining RNF5 effect on gut microbiota.

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