Abstract
Ubiquitin (Ub) and ubiquitin-like (UBL) proteins regulate a diverse array of cellular pathways through covalent as well as non-covalent interactions with target proteins. Yeast protein Mdy2 (Get5) and its human homolog GdX (Ubl4a) belong to the class of UBL proteins which do not form conjugates with other proteins. Mdy2 is required for cell survival under heat stress and for efficient mating. As part of a complex with Sgt2 and Get4 it has been implicated in the biogenesis of tail-anchored proteins. Interestingly, in response to heat stress, Mdy2 protein that is predominantly localized in the nucleus co-localized with poly(A)-binding protein Pab1 to cytoplasmic stress granules suggesting that nucleocytoplasmic shuttling is of functional importance. Here we investigate the nuclear import of Mdy2, a process that is independent of the Get4/Sgt2 complex but required for stress response. Nuclear import is mediated by an N-terminal nuclear localization signal (NLS) and this process is essential for the heat stress response. In contrast, cells expressing Mdy2 lacking a nuclear export signal (NES) behave like wild type. Importantly, both Mdy2 and Mdy2-ΔNES, but not Mdy2-ΔNLS, physically interact with Pab1 and this interaction correlates with the accumulation in cytoplasmic stress granules. Thus, the nuclear history of the UBL Mdy2 appears to be essential for its function in cytoplasmic stress granules during the rapid cellular response to heat stress.
Highlights
Ubiquitin-like (UBL) proteins with their characteristic ubiquitin-like polypeptides (UBLs) domain are involved in a wide range of cellular processes, such as targeting and formation of nuclear compartments, spindle pole body duplication, and apoptosis
Double deletion strains of mdy2Dget4D or mdy2Dsgt2D exhibit no synergistic sensitivity (Figure 1A)
We identified three potential candidates for classical nuclear localization signal (NLS), which are rich in lysine and arginine
Summary
Ubiquitin-like (UBL) proteins with their characteristic UBL domain are involved in a wide range of cellular processes, such as targeting and formation of nuclear compartments, spindle pole body duplication, and apoptosis. Ubiquitin-like proteins are divided into two subclasses [1]. Type-1 ubiquitin-like polypeptides (UBLs) essentially consist only of the UBL domain and function as modifiers like ubiquitin, being ligated to target proteins in a process similar to ubiquitylation. Important examples are SUMO, NEDD8, and UCRP/ISG15. In type-2 proteins the UBL domain is accompanied by other domains suggesting different functions. This is supported by the observation that type-2 proteins do not form covalent conjugates with target proteins [1,2]
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