Critical roles of FAM134B in ER-phagy and diseases

Abstract

FAM134B (also called JK-1, RETREG1), a member of the family with sequence similarity 134, was originally discovered as an oncogene in esophageal squamous cell carcinoma. However, its most famous function is that of an ER-phagy-regulating receptor. Over the decades, the powerful biological functions of FAM134B were gradually revealed. Overwhelming evidence indicates that its dysfunction is related to pathophysiological processes such as neuropathy, viral replication, inflammation, and cancer. This review describes the biological functions of FAM134B, focusing on its role in ER-phagy. In addition, we summarize the diseases in which it is involved and review the underlying mechanisms.

Fig. 1. FAM134B is characterized by two important domains: the RHD and the LIR.

The RHD contains two transmembrane segments (TM1–2, TM3–4, green), which are bridged by a flexible linker, and two additional terminal segments. The C-terminal segment and partial linker form amphipathic helices (AHL, AHC, gray). Three phosphorylation sites (S149, S151, and S153; orange) in the RHD are involved in protein oligomerization. Mutations of Q145 and cleavage sites of ZIKV R142X reside in the RHD, producing a truncated protein (yellow). The genetic variant G216R is a gain-of-function mutant causing excessive ER-phagy (yellow). The S309X product lacks the LIR motif so that it cannot interact with LC3-like proteins (red dotted line).

Fig. 2. In ER-phagy, FAM134B senses and induces ER membrane curvature via the RHD.

In the meantime, LIR binds to the autophagosome generating a pulling force, so that the ER membrane forms vesicles, which pinch off and are then engulfed by the phagophore. CAMK2B phosphorylates FAM134B leading to oligomerization, ER fragmentation, and ER-phagy. High levels of AMFR lead to destabilized OMM and exposed IMM. FAM134B promotes the formation of the mitophagophore by interacting with OPA1. Besides, by potentiating mitophagy, it improves preadipocytes differentiation. CANX recognizes misfolded procollagens and interacts with FAM134B. Next, FAM134B binds to the autophagosome and delivers cargos to the lysosome for degradation. ATZ polymers are degraded through the ERLAD pathway. In this process, FAM134B helps the polymers enter the vesicles from the ER domain, and promotes the docking of these ER-derived vesicles to lysosomes. CANX segregates ATZ polymers into ER subdomains and forms a CNX:FAM134B:LC3B complex for the next step. In the liver, starvation induces C/EBPβ expression, which then increases the expression of FAM134B-2. FAM134B-2 interacts with LC3B and its lysosomal degradation is increased under starvation, indicating that it plays a role in starvation-induced hepatic ER-phagy.

Fig. 3. Mutations of FAM134B disturb ER-phagy and may cause alterations of Golgi structure.

Related pathological processes might break the homeostasis of neural cells, leading to the progression of HSAN II. FAM134B obstructs the replication of DENV, ZIKV, and EBOV. Consequently, DENV and ZIKV cleave FAM134B to subvert ER-phagy. FAM134B acts as an oncogene in HCC and ESCC, but it plays a tumor suppressor role in CRC. In HCC, FAM134B activates the Akt signaling pathway, promoting cell proliferation and metastasis. In CRC, FAM134B is not only located in the cytoplasm but also in the nucleus. However, the role it plays in the nucleus is still unclear. FAM134B and TNFRSF19 show a strong synergy in vascular dementia. Their effect may be related to their roles in the Golgi apparatus. In AR, the expression of CD39 on Treg cells is negatively correlated with the expression of FAM134B on monocytes. The CD39 expressed by Treg cells can hydrolyze extracellular ATP to suppress asthmatic airway inflammation. However, ATP can increase the expression levels of FAM134B in CD4⁺ blood monocytes. Thus, ATP may be a link between CD39 and FAM134B in AR.

Fig. 4. In HCC, FAM134B activates Akt to induce GSK3-β phosphorylation and subsequent dysfunction.

GSK3-β phosphorylates β-catenin and Snail, leading to their degradation. Thus, by activating Akt, FAM134B inactivates GSK3-β, stabilizes β-catenin, and Snail. On the one hand, the increasing β-catenin translocates into the nucleus and interacts with TCF/LEF to increase the expression of CyclinD1 to promote cell proliferation. On the other hand, Snail suppresses E-cadherin expression via directly impinging on its promoter to trigger EMT in the nucleus.