RNF4—A Paradigm for SUMOylation‐Mediated Ubiquitination

Abstract

Covalent modifications by Small Ubiquitin‐like MOdifier (SUMO) and ubiquitin conjugation are now recognized as independent posttranslational modifications (PTMs) employed by cells to reversibly regulate cellular signaling. SUMOylation in particular has emerged as a crucial cellular mechanism involved in multiple pathologies, including cancers, cardiovascular diseases, immunological and neurological disorders, as well as aging. Convergence of these two PTMs result in the ubiquitination of SUMOylated proteins, adding complexity in the modulation of protein functions. The SUMO‐Targeted Ubiquitin Ligases (STUbL) mediate this process, and RNF4, the mammalian STUbL, has been at the forefront in the understanding of this phenomenon. It has been shown to play important roles in a variety of cellular events, ranging from the maintenance of genomic integrity and hence, oncogenesis, to a role in development. Recent identification of direct and indirect RNF4 targets has revealed that the SUMOylation machinery is in itself targeted by RNF4, highlighting the complex nature of the signaling circuitry tightly regulating these processes. This review will touch upon both SUMOylation and ubiquitination, and will focus on how RNF4, which is at the heart of both these PTMs, modulates cellular signaling and promotes protein degradation. Moreover, the potential of therapeutically targeting RNF4 to improve cancer treatment is also explored.

SUMO and Transcriptional Regulation: The Lessons of Large-Scale Proteomic, Modifomic and Genomic Studies

“…If the main category of substrates is the SUMOylation machinery itself, many of the other substrates deal with nucleic acids biology. The main processes characterized include DNA repair, which is consistent with the documented role of RNF4 in this process [122], but also transcription, by affecting factors interacting with, or contributing to, the TFIID complex and the Pol II machinery [121]. Transcription factors such as Sp1 [123] or Myc [124] are also concerned.…”

SUMO Chains Rule on Chromatin Occupancy

“…In both lower and higher eukaryotes StUBLs contribute to the maintainance of genome stability (Heideker et al, 2009;Kumar and Sabapathy, 2019). A recurrent theme in DDR pathways is the SUMO-regulated turnover of repair factors at sites of DNA damage.…”

“…In this evolutionary conserved pathway, poly-(or multi-) SUMOylated proteins are recognized by E3 ubiquitin ligases that contain specific binding modules for these structures. The best-characterized StUbLs are the budding yeast Slx5/Slx8 heterodimer and the mammalian RING-type ubiquitin ligases RNF4 and RNF111 (Sriramachandran and Dohmen, 2014;Kumar and Sabapathy, 2019). They all contain poly-or multi-SUMO binding modules and catalyze either non-proteolytic or proteolytic ubiquitylation of proteins modified by multiple SUMO moieties.…”

Crosstalk Between SUMO and Ubiquitin-Like Proteins: Implication for Antiviral Defense

“…However, alternatively linked non-canonical SUMO2/3 chains, mixed SUMO1-SUMO2/3 chains and SUMO2/3 chains capped with SUMO2, have been described ( Sriramachandran and Dohmen, 2014 ; Gartner et al, 2018 ; Sriramachandran et al, 2019 ). It is well established that SUMO2/3 have the capability to efficiently form highly branched poly-SUMO chains that have the ability to recruit SUMO-targeted ubiquitin ligases (STUbls) such as the RING finger protein RNF4 and RNF111 ( Sriramachandran and Dohmen, 2014 ; Kumar and Sabapathy, 2019 ). RNF4 harbors multiple SIMs in its N-terminus region that allow a strong interaction with SUMO leading to the ubiquitylation of poly-SUMO chains conjugated to substrates and resulting in the proteasomal degradation of SUMO2/3 conjugated proteins ( Hay, 2013 ).…”