Curvature induction and membrane remodeling by FAM134B reticulon homology domain assist selective ER-phagy

Abstract

FAM134B/RETREG1 is a selective ER-phagy receptor that regulates the size and shape of the endoplasmic reticulum. The structure of its reticulon-homology domain (RHD), an element shared with other ER-shaping proteins, and the mechanism of membrane shaping remain poorly understood. Using molecular modeling and molecular dynamics (MD) simulations, we assemble a structural model for the RHD of FAM134B. Through MD simulations of FAM134B in flat and curved membranes, we relate the dynamic RHD structure with its two wedge-shaped transmembrane helical hairpins and two amphipathic helices to FAM134B functions in membrane-curvature induction and curvature-mediated protein sorting. FAM134B clustering, as expected to occur in autophagic puncta, amplifies the membrane-shaping effects. Electron microscopy of in vitro liposome remodeling experiments support the membrane remodeling functions of the different RHD structural elements. Disruption of the RHD structure affects selective autophagy flux and leads to disease states.

Regulation of Phosphoribosyl-Linked Serine Ubiquitination by Deubiquitinases DupA and DupB

“…oligomerization of reticulon proteins may play a critical role in triggering the ability of FAM134 and RTN3 to fragment ER (Grumati et al, 2017;Khaminets et al, 2015). This may be assisted with the special arrangement of transmembrane insertions of the reticulon domain that are predisposing lipid bilayers for membrane curvature (Bhaskara et al, 2019). Interestingly, oligomerization of FAM134C and TEX264 correlate with their PR ubiquitination .…”

Reticulon Homology Domain-Containing Proteins and ER-Phagy

“…Interestingly, the capability of FAM134B to sense and induce membrane curvature during ER-phagy is strictly dependent on its RHD structure and topology, which are fundamental for the capability of the protein to regulate membrane remodeling and ER degradation. This notion is supported by the fact that RHD disruption affects selective ER-phagy flux and is associated with pathological states (Bhaskara et al, 2019).…”

Autophagy and Viral Infection

“…Zika virus (ZIKV) utilizes the ER as a source of membranes to establish their viral replication, assembly and maturation. A selective form of ER degradation by autophagy, or reticulophagy has evolved in the host to restrict DENV and ZIKV, mediated by an ER-resident reticulophagy receptor FAM134B [7]. The virally encoded proteases NS3 in several flaviviruses including ZIKV, DENV, and West Nile Virus (WNV) cleaves FAM134B to suppress the formation of ER and viral protein enriched autophagosomes, as a strategy that viruses manipulate autophagy for their replication (Fig.…”