Endoplastic reticulum (ER)은 membrane에 싸여 있는 세포내 소기관으로 모든 진핵생물에 존재하며 단백질의 folding, lipid와 sterol의 생성 그리고 calcium의 보관의 역할을 수행한다. Unfolded protein response (UPR)은 이와 같은 기능을 수행하는 ER의 기능저하를 감지하는 여러 가지 신호전달체계를 총칭하는 말로써 ER stress에 따른 세포의 사멸 또는 생존의 반응을 결정하는 역할을 갖게 된다. UPR은 ER의 기능을 보호하기 위하여 ER의 단백질 folding 능력 향상, 잘못 folding된 단백질의 분해 그리고 전반적인 단백질 생성저하 등을 유도하나, 고지방식이 섭취에 의한 비만과 같은 만성적 ER stress유발 상황에서는 인슐린 저항성 유발 및 보다 심각한 대사질환을 일으킬 수 있는 주요 기전으로 보고되고 있다. 본 종설에서는 비만에 의해 유발되는 생리학적 만성 ER stress유발에 따른 대사질환의 분자적 기전에 대해 고찰하고자 한다.

비만과 ER Stress

Eukaryotes have evolved various quality control mechanisms to promote proteostasis in the endoplasmic reticulum (ER). Selective removal of certain ER domains via autophagy (termed as ER-phagy) has emerged as a major quality control mechanism. However, the degree to which ER-phagy is employed by other branches of ER-quality control remains largely elusive. Here, we identify a cytosolic protein, C53, that is specifically recruited to autophagosomes during ER-stress, in both plant and mammalian cells. C53 interacts with ATG8 via a distinct binding epitope, featuring a shuffled ATG8 interacting motif (sAIM). C53 senses proteotoxic stress in the ER lumen by forming a tripartite receptor complex with the ER-associated ufmylation ligase UFL1 and its membrane adaptor DDRGK1. The C53/UFL1/DDRGK1 receptor complex is activated by stalled ribosomes and induces the degradation of internal or passenger proteins in the ER. Consistently, the C53 receptor complex and ufmylation mutants are highly susceptible to ER stress. Thus, C53 forms an ancient quality control pathway that bridges selective autophagy with ribosome-associated quality control in the ER.

A cross-kingdom conserved ER-phagy receptor maintains endoplasmic reticulum homeostasis during stress

Protein Quality Control in Plant Organelles: Current Progress and Future Perspectives.

ER-phagy responses in yeast, plants, and mammalian cells and their crosstalk with UPR and ERAD.

Eukaryotes have evolved various quality control mechanisms to promote proteostasis in the ER. Selective removal of certain ER domains via autophagy (termed as ER-phagy) has emerged as a major quality control mechanism. However, the degree to which ER-phagy is employed by other branches of ER-quality control remains largely elusive. Here, we identify a cytosolic protein, C53, that is specifically recruited to autophagosomes during ER-stress, in both plant and mammalian cells. C53 interacts with ATG8 via a distinct binding epitope, featuring a shuffled ATG8 interacting motif (sAIM). C53 senses proteotoxic stress in the ER lumen by forming a tripartite receptor complex with the ER-associated ufmylation ligase UFL1 and its membrane adaptor DDRGK1. The C53/UFL1/DDRGK1 receptor complex is activated by stalled ribosomes and induces the degradation of internal or passenger proteins in the ER. Consistently, the C53 receptor complex and ufmylation mutants are highly susceptible to ER stress. Thus, C53 forms an ancient quality control pathway that bridges selective autophagy with ribosome-associated quality control at the ER.

https://www.biorxiv.org/content/biorxiv/early/2020/03/24/2020.03.18.995316.full.pdf

Reticulon (Rtn) proteins shape tubular domains of the endoplasmic reticulum (ER), and in some cases are autophagy receptors for selective ER turnover. We have found that maize Rtn1 and Rtn2 control ER homeostasis and autophagic flux in endosperm aleurone cells, where the ER accumulates lipid droplets and synthesizes storage protein accretions metabolized during germination. Maize Rtn1 and Rtn2 are expressed in the endosperm, localize to the ER, and re-model ER architecture in a dose-dependent manner. Rtn1 and Rtn2 interact with Atg8a using four Atg8-interacting motifs (AIMs) located at the C-terminus, cytoplasmic loop, and within the transmembrane segments. Binding between Rtn2 and Atg8 is elevated upon ER stress. Maize rtn2 mutants display increased autophagy and up-regulation of an ER stress-responsive chaperone. We propose that maize Rtn1 and Rtn2 act as receptors for autophagy-mediated ER turnover, and thus are critical for ER homeostasis and suppression of ER stress.

/pdf/reticulon-proteins-modulate-autophagy-of-the-endoplasmic-3re4bblrq0.pdf

Patrick Lacey

Papers

Reticulon proteins modulate autophagy of the endoplasmic reticulum in maize endosperm

Author response: Reticulon proteins modulate autophagy of the endoplasmic reticulum in maize endosperm