9.B.362.  The FAM134 Reticulon Protein (FAM134) Family

The endoplasmic reticulum (ER) is the largest intracellular endomembrane system, enabling protein and lipid synthesis, ion homeostasis, quality control of newly synthesized proteins and organelle communication. Constant ER turnover and modulation is needed to meet different cellular requirements, and autophagy has an important role in this process. Khaminets et al. 2015 showed that members of the FAM134 reticulon protein family are ER-resident receptors that bind to autophagy modifiers LC3 and GABARAP, and facilitate ER degradation by autophagy ('ER-phagy'). Downregulation of the FAM134B protein in human cells causes an expansion of the ER, while FAM134B overexpression results in ER fragmentation and lysosomal degradation. Mutant FAM134B proteins that cause sensory neuropathy in humans are unable to act as ER-phagy receptors. Consistently, disruption of Fam134b in mice causes expansion of the ER, inhibits ER turnover, sensitizes cells to stress-induced apoptotic cell death and leads to degeneration of sensory neurons. Therefore, selective ER-phagy via FAM134 proteins is indispensable for mammalian cell homeostasis and controls ER morphology and turnover in mice and humans (Khaminets et al. 2015). 

Selective autophagy of the endoplasmic reticulum (termed ER-phagy) is controlled by members of the FAM134 reticulon protein family. Chiramel et al. 2016 used mouse embryonic fibroblasts from mice deficient in FAM134B to examine the role of the ER in replication of historic (Mayinga) or contemporary (Makona GCO7) strains of Ebola virus (EBOV). Loss of FAM134B resulted in 1-2 log10 higher production of infectious EBOV, which was associated with increased production of viral proteins GP and VP40 and greater accumulation of nucleocaspid lattices. In addition, only 10% of wild-type cells contained detectable nucleoprotein, whereas knockout of FAM134B resulted in 80% of cells positive for nucleoprotein. Together, these data suggest that FAM134B-dependent ER-phagy is an important limiting event in EBOV replication in mouse cells (Chiramel et al. 2016). 

FAM134B), is a cis-Golgi transmembrane protein that is necessary for the long-term survival of nociceptive and autonomic ganglion neurons. FAM134B plays a pivotal role in autophagy-mediated turnover of ER membranes, tumor inhibition and lipid homeostasis. Cai et al. 2019 provided mechanistic links between FAM134B and ARF-related protein 1 (ARFRP1) and showed that FAM134B resides in the Golgi apparatus. They found that FAM134B increased lipid accumulation in adipocytes. Transport vehicle number and ADP-ribosylation factor (ARF) family gene expression were also increased by FAM134B overexpression, suggesting that vesicular transport activity enhanced lipid accumulation. ARF-related protein 1 (ARFRP1) is a GTPase that promotes protein trafficking. They showed that FAM134B regulates the expression of ARFRP1, and the knockdown of ARFRP1 abolished enhancement on lipid accumulation caused by FAM134B. In addition, FAM134B upregulated the PAT family protein (PAT), which associates with lipid droplet (LD) surfaces and promotes lipolysis by recruiting adipocyte triglyceride lipase (ATGL). These findings indicate that FAM134B promotes lipid accumulation and adipogenic differentiation by increasing vesicle transport activity in the Golgi apparatus and inhibiting the lipolysis of LDs (Cai et al. 2019).




Cai, M., J. Chen, C. Yu, L. Xi, Q. Jiang, Y. Wang, and X. Wang. (2019). FAM134B promotes adipogenesis by increasing vesicular activity in porcine and 3T3-L1 adipocytes. Biol Chem 400: 523-532.

Chiramel, A.I., J.D. Dougherty, V. Nair, S.J. Robertson, and S.M. Best. (2016). FAM134B, the Selective Autophagy Receptor for Endoplasmic Reticulum Turnover, Inhibits Replication of Ebola Virus Strains Makona and Mayinga. J Infect Dis 214: S319-S325.

Khaminets, A., T. Heinrich, M. Mari, P. Grumati, A.K. Huebner, M. Akutsu, L. Liebmann, A. Stolz, S. Nietzsche, N. Koch, M. Mauthe, I. Katona, B. Qualmann, J. Weis, F. Reggiori, I. Kurth, C.A. Hübner, and I. Dikic. (2015). Regulation of endoplasmic reticulum turnover by selective autophagy. Nature 522: 354-358.

Yang, Y. and D.J. Klionsky. (2020). A novel reticulophagy receptor, Epr1: a bridge between the phagophore protein Atg8 and ER transmembrane VAP proteins. Autophagy 1-2. [Epub: Ahead of Print]


TC#NameOrganismal TypeExample

The FAM134B protein, RETREG1, of 497 aas and 4 TMSs in a 2 + 2 arrangment. It can serve as a reticulophagy receptor (Yang and Klionsky 2020).

FAM134B of Homo sapiens


Reticulophagy regulator 3, RR3, of 464 aas and 4 N-terminal TMSs

RR3 of Exaiptasia pallida


Uncharacterized protein of 376 aas and 4 N-terminal TMSs in a 2 + 2 TMS arrangement.

UP of Asbolus verrucosus


Reticulophagy regulator 3 of327 aas and 4 N-terminal TMSs

RR3 of Diachasma alloeum


ADP-ribosylation factor-like protein 6-interacting protein 1 isoform X1 of 207 aas and 4 TMSs in a 2 + 2 TMS arrangement.

ADP-ribosylation factor of Pomacea canaliculata


Reticulophagy regulator 2 of 430 aas and 4 N-terminal TMSs in a 2 + 2 TMS arrangement.

RR2 of Bagarius yarrelli


Uncharacterized protein of 296 aas and 4 or 5 TMSs in a 2 + 2 or 3 TMS arrangement.

UP of Opisthorchis felineus