Signaling Regulation of FAM134-Dependent ER-Phagy in Cells

Abstract

The endoplasmic reticulum (ER) is a pivotal organelle responsible for protein and lipid synthesis, calcium homeostasis, and protein quality control within eukaryotic cells. To maintain cellular health, damaged or excess portions of the ER must be selectively degraded via a process known as selective autophagy, or ER-phagy. This specificity is driven by a network of protein receptors and regulatory mechanisms. In this review, we explore the molecular mechanisms governing ER-phagy, with a focus on the FAM134 family of ER-resident ER-phagy receptors. We discuss the molecular pathways and Posttranslational modifications that regulate receptor activation and clustering, and how these modifications fine-tune ER-phagy in response to stress. This review provides a concise understanding of how ER-phagy contributes to cellular homeostasis and highlights the need for further studies in models where ER stress and autophagy are dysregulated.

Keywords: ER‐phagy; FAM134B; autophagy; endoplasmic reticulum; ubiquitination.

Figure 1

Roles of FAM134 protein family. The figure shows the most important roles of FAM134A, B and C (left), as well as the recently identified truncated form of FAM134B (FAM134B‐2, right). The LC3‐interacting region (LIR) domain is highlighted in red.

Figure 2

Signaling pathways converging on FAM134B promote its clustering into homomeric and heteromeric protein complexes. (a) The ubiquitination mechanism of FAM134B/C leads to homo/hetero cluster formation that drives ER‐phagy. (b) Imbalances in nutrient availability serve as critical stimuli that trigger the massive expression of FAM134B. In this context, CK2 phosphorylates the ER‐resident FAM134B at specific residues within the RHD domain, marking the protein for subsequent ubiquitination by AMFR. In its activated form, FAM134B nucleates to form heteromeric protein clusters. (c) Acetylation serves to prime FAM134B for phosphorylation and subsequent modulation of ER‐phagy. (d) Transcriptional mechanism of ER‐phagy regulation induced by the modulation of SESTRIN2 and TFEB/TFE3 nuclear translocation. ER, endoplasmic reticulum; RHD, reticulon homology domain.