The Paf1 complex transcriptionally regulates the mitochondrial-anchored protein Atg32 leading to activation of mitophagy

Abstract

Mitophagy is a critical process that safeguards mitochondrial quality control in order to maintain proper cellular homeostasis. Although the mitochondrial-anchored receptor Atg32-mediated cargo-recognition system has been well characterized to be essential for this process, the signaling pathway modulating its expression as a contribution of governing the mitophagy process remains largely unknown. Here, bioinformatics analyses of epigenetic or transcriptional regulators modulating gene expression allow us to identify the Paf1 complex (the polymerase-associated factor 1 complex, Paf1C) as a transcriptional repressor of ATG genes. We show that Paf1C suppresses glucose starvation-induced autophagy, but does not affect nitrogen starvation-or rapamycin-induced autophagy. Moreover, we show that Paf1C specifically regulates mitophagy through modulating ATG32 expression. Deletion of the genes encoding two core subunits of Paf1C, Paf1 and Ctr9, increases ATG32 and ATG11 expression and facilitates mitophagy activity. Although Paf1C is required for many histone modifications and gene activation, we show that Paf1C regulates mitophagy independent of its positive regulatory role in other processes. More importantly, we also demonstrate the mitophagic role of PAF1C in mammals. Overall, we conclude that Paf1C maintains mitophagy at a low level through binding the promoter of the ATG32 gene in glucose-rich conditions. Dissociation of Paf1C from ATG32 leads to the increased expression of this gene, and mitophagy induction upon glucose starvation. Thus, we uncover a new role of Paf1C in modulating the mitophagy process at the transcriptional level.

Mitochondrial clearance: mechanisms and roles in cellular fitness

“…In cells lacking PpSin3 and PpRpd3, PpAtg32 is induced without starvation signals, suggesting that the Tor-Sin3-Rpd3 axis contributes to downregulation of PpAtg32 expression. Moreover, a recent study showed that loss of the Paf1 (RNA polymerase Ⅱ-associated factor 1) complex, a highly conserved complex involved in transcription elongation, leads to global upregulation of ATG genes including ATG32 and ATG11, and induction of mitophagy [36].…”

Mitophagy in Yeast: Decades of Research

“…For its importance, Atg32 expression and activity are subject to precise complex regulation. At the transcription level, several repressors [ 49 , 50 ] and activators [ 51 , 52 , 53 ] were described to control or link with Atg32 expression. An additional mechanism for conducting mitophagy induction is Atg32 phosphorylation [ 54 , 55 , 56 ].…”

“…In both scenarios, the presence of Atg32p is required. Atg32p is constantly present in the outer membrane of the mitochondria and must be phosphorylated by casein kinase 2 (CK2) for mitophagy to be induced [ 50 ]. At present, Atg11 and Atg8 are the only two proteins identified that interact with Atg32p.…”

The PAF1 complex cell-autonomously promotes oogenesis in Caenorhabditis elegans

“…Additionally, the PAF1C affects Notch, Wnt, and Hedgehog signaling [8,[12][13][14]. The PAF1C has also been reported to regulate the proliferation, differentiation, morphology, cell migration, epidermal morphogenesis, mitophagy, maintenance of stem cells, and tumorigenesis [4,10,[15][16][17][18][19][20][21][22][23]. However, the functional importance of the PAF1C in germ cell development has not yet been explored.…”