The Role of the Transmembrane RING Finger Proteins in Cellular and Organelle Function

Abstract

A large number of RING finger (RNF) proteins are present in eukaryotic cells and the majority of them are believed to act as E3 ubiquitin ligases. In humans, 49 RNF proteins are predicted to contain transmembrane domains, several of which are specifically localized to membrane compartments in the secretory and endocytic pathways, as well as to mitochondria and peroxisomes. They are thought to be molecular regulators of the organization and integrity of the functions and dynamic architecture of cellular membrane and membranous organelles. Emerging evidence has suggested that transmembrane RNF proteins control the stability, trafficking and activity of proteins that are involved in many aspects of cellular and physiological processes. This review summarizes the current knowledge of mammalian transmembrane RNF proteins, focusing on their roles and significance.

Figure 1

Schematic representations of the ubiquitination reaction and the RNF domain structures. (A) The biochemical steps in ubiquitination are illustrated. Ub is activated at its C-terminal glycine residue (Gly76) in an ATP-dependent manner by E1. In an ATP-hydrolyzing reaction, a Ub adenylate intermediate is formed, followed by the binding of Ub to a specific cysteine residue of E1. Ub is then transferred to an active site cysteine residue of E2, preserving the high energy thioester bond. The substrate is recognized by E3, which also recruits the E2–Ub complex. Finally, Ub is linked by its C-terminus in an isopeptide linkage to an ε-amino group of lysine residues on the substrate protein. (B) A simple comparison of the cross-brace arrangements of the RING-H2, RING-HC and RING-CH finger motifs. C and H indicate the conserved Zn²⁺-coordinating cysteine and histidine residues.

Figure 2

Phylogenetic analysis of putative human transmembrane RNF proteins. The tree was constructed by the neighbor-joining method with ClustalW [22] and MEGA4 [23] using 5,000 bootstrap resamplings. The scale bar indicates 0.2 amino acid substitutions per each amino acid position. Members of the TRIM, PA-TM-RING, MARCH and RBR families are indicated in green, red, blue and purple fonts, respectively.

Figure 3

Comparison of the domain structures of putative human transmembrane RNF proteins. Information on the domain structure of each RNF protein was obtained from the ENSEMBL (http://www.ensembl.org [28]) and NCBI (http://www.ncbi.nlm.nih.gov [29]) databases. Abbreviations: PA, protease-associated domain; TM, putative transmembrane domain; CUE, coupling of Ub conjugation to ER degradation; SAM, sterile alpha motif; DED, death effecter domain.

Figure 4

Schematic diagram of the organization of organelles and the intracellular transport pathways. The major membrane-bound organelles and the main routes of protein transport are indicated, with the secretory pathway in green, the endocytic degradation pathway in black, the recycling pathway in red and the retrograde pathway in blue.

Figure 5

Proposed roles of the transmembrane RNF proteins in mitochondrial dynamics and mitophagy. MARCH5 may regulate mitochondrial fusion and fission by ubiquitinating MFN1 and DRP1. MAPL SUMO ligase stabilizes DRP1 and therefore promotes mitochondrial fission. RNF185-mediated ubiquitination triggers mitophagy.