The transcription factor Spt4-Spt5 complex regulates the expression of ATG8 and ATG41

Abstract

Macroautophagy/autophagy, a highly conserved dynamic process, is one of the major degradative pathways in cells. So far, over 40 autophagy-related (ATG) genes have been identified in Saccharomyces cerevisiae, most of which have homologs in more complex eukaryotes. Autophagy plays a crucial role in cell survival and maintenance, and its dysfunction is related to various diseases, indicating that the proper regulation of autophagy is important. Although the overall process of autophagy has been extensively studied, in particular with regard to the function of the Atg proteins, relatively little is known about the regulatory mechanisms that control autophagy activity. Spt5 is one of the transcriptional factors that is universally conserved across all domains. This protein can form a complex with Spt4, together playing a central role in transcription. In complex eukaryotic cells, the Spt4-Spt5 complex plays a dual role in gene regulation, acting both to delay transcription through promoter-proximal pausing, and to facilitate transcriptional elongation. In contrast, in S. cerevisiae, only the positive function of the Spt4-Spt5 complex has been identified. Here, we show for the first time that the Spt4-Spt5 transcription factor complex negatively regulates ATG genes in S. cerevisiae, inhibiting autophagy activity during active growth. Under autophagy-inducing conditions, the repression is released by Spt5 phosphorylation, allowing an upregulation of autophagy activity.

The transient Spt4-Spt5 complex as an upstream regulator of non-coding RNAs during development

“…However, other studies showing a role of Spt5 in early transcription proved that neither the Spt5 CTR (C’-terminal repeats) domain, which can be phosphorylated, nor the Spt4 partner are important for promoter escape ( 65 ). Interestingly, Spt4 was shown to play a role in autophagy as an inhibitor of Spt5 phosphorylation ( 16 ) and it is possible that it is also necessary for the progression of meiosis. This putative role of Spt4 is especially interesting because of the evidence indicating that dephosphorylation of Spt5 decreases the elongation rate of the RNA Pol II complex ( 66 ).…”

“…As an example, Spt5 is involved in RNA maturation, whereas Spt4 is involved in chromosome transmission and the assembly of centromere heterochromatin ( 12–15 ). Furthermore Spt4 functions as a negative regulator of autophagy through inhibition of Spt5 phosphorylation, suggesting that their roles do not necessarily overlap ( 16 ).…”

Downregulation of autophagy by Met30-mediated Atg9 ubiquitination

“…Sample Preparation and Mass Spectrometry. Purified ATG9 was directly digested on beads overnight according to the filter-aided sample preparation (FASP) protocol, and the analysis was carried out essentially as described previously (49).…”

Old factors, new players: transcriptional regulation of autophagy

“…Upon deletion of SPT4, Wen et al found an increase in both mRNA and protein levels of ATG8/Atg8 and ATG41/Atg41 in nutrient-rich conditions. Moreover, cells lacking Spt4 display increased autophagy activity, suggesting Spt4 negatively regulates autophagy [7].…”