DEG_Cend_TRIM7_1

The genome can be subject to various types of damage, such as germline mutations, replication errors and more. The mRNA molecules can also be mis-processed or translated erroneously. In addition, protein molecules can suffer chemical damage (e.g. hydrolysis) as they age. Protein quality control is a vital cellular process that ensures the proper folding, assembly, and function of proteins. It involves various surveillance mechanisms that detect misfolded or damaged proteins and either facilitate their refolding or target them for degradation via protein degradation pathways such as the ubiquitin-proteasome system, thereby maintaining cellular homeostasis (Yeh,2021).
C-degron pathways have been implicated in various biological processes, including protein quality surveillance, cell cycle regulation, antiviral defence, and signal transduction. Dysregulation of C-degron pathways can lead to the accumulation of abnormal or misfolded proteins, contributing to the development of human diseases such as neurodegenerative disorders (Chen,2021).
C-terminal degrons can be present in full length proteins internally, in which case they must be revealed by proteolytic cleavage. On the other hand, they can be natively present at the C-termini of other proteins or even introduced by premature translation termination.
The TRIM7 ubiquitin ligase recognizes proteins ending in the phenylalanine-glutamine or leucine-glutamine sequence. Experimentally determined structures show that the peptides are bound to the B30.2/SPRY domain in a helical conformation. Similar to other members of the TRIM ubiquitin ligase family, TRIM7 is also considered to play a role in innate immunity by acting as an antiviral effector. Although, only a few known full length cellular substrates ending in the FQ or LQ sequence have been identified (most notably, glycogenin and E3 ligase RNF187), such sites are frequently observed in the proteins of RNA viruses (Ru,2022). Many RNA viruses encode long polyproteins that are cleaved to individual structural and non-structural proteins by glutamine-directed proteases, generating potential TRIM7 substrates. Hence TRIM7 can effectively restrict viral replication by targeting at least a subset of the viral polyprotein cleavage products to ubiquitin-dependent degradation. However, TRIM7′s restricted tissue expression (at least in humans) and lack of immune regulation suggests that viral restriction may or may not be its physiological function (Q9C029, Luptak,2022). For example, in striated muscle, it might be involved in regulating glycogen formation by targeting glycogenin (Skurat,2002).
TRIM7 is mostly involved in the K48-linked polyubiquitylation (triggering proteasome-dependent degradation) of most of its substrates, except for RNF187 (also known as RACO-1). On this latter substrate (which is also an ubiquitin ligase itself), TRIM7 aids the assembly of immune-activating, K63-linked polyubiquitin chains (Chakraborty,2015).
While many RNA virus polyprotein cleavage sites (typically cleaved after glutamine) were found to be potential TRIM7 substrates, these targets are mostly featured in their uncleaved precursor form in the UniProt database. This precludes automatic detection of putative viral substrate proteins, as proteolytic sites need to be mapped and verified first.
RNA virus protein entries in UniProt are for the full length polyprotein. Therefore the C-degrons for the cleaved products shown in ELM do not correspond to the actual C-terminus of the UniProt sequence. Additional instances which are missing from the instance table are Coxsackievirus B3 Genome polyprotein (P03313, 1428-1429 (7Y3A)), SARS2 Replicase polyprotein (P0DTD1, 3568-3569 (7x6y); 4139-4140 (7x70), and Murine norovirus 1 Genome polyprotein (Q80J95, 704-705 (8a8x).