细胞生物.9 | ER
1. Endomembrane System 内膜系统
EN: The endomembrane system is a group of interconnected membrane-bound organelles that work together to modify, package, and transport lipids and proteins.
CN: 内膜系统是由一系列膜性细胞器组成的网络，彼此相连或通过囊泡运输，主要负责修饰、包装和运输脂质及蛋白质。
Includes 包括:
- Plasma Membrane (质膜)
- Endoplasmic Reticulum (内质网, ER)
- Golgi Apparatus (高尔基体)
- Lysosomes (溶酶体)
- Vesicles/Endosomes (囊泡/内体)
- Vacuoles (液泡)
2. Endoplasmic Reticulum (ER, 内质网)
EN: ER is a network of flattened sacs (cisternae) enclosed by a lipid bilayer, continuous with the outer membrane of the nuclear envelope, and highly dynamic.
CN: 内质网是由扁平囊（cisternae）**组成的网络，包裹在**脂双层膜**中，与核膜外层相连，并且是一个高度动态、不断重组的结构**。
3. ER Subtypes 内质网的分类
Rough ER (RER, 粗面内质网)
- EN: Has ribosomes on its surface; consists of many stacked flattened sacs; specialized for protein synthesis (especially secretory and membrane proteins).
- CN: 表面附着核糖体；结构为多层堆叠的扁平囊；功能是合成分泌蛋白和膜蛋白。
Smooth ER (SER, 光面内质网)
- EN: Lacks ribosomes; tubular network; functions include lipid synthesis, detoxification, and calcium storage.
- CN: 没有核糖体；结构为管状网络；功能包括脂质合成、解毒、钙储存等。
4. Similarities and Differences 异同点
Similarities 相同点
- EN: Their membranes are continuous and they share some proteins and functions.
- CN: 两者的膜是连续的，并且共享部分蛋白和功能。
Differences 不同点
- Structure 结构: RER = stacked sacs (叠层扁囊), SER = tubules (管状网络)
- Ribosomes 核糖体: RER has them (有), SER does not (无)
- Distribution 分布: RER abundant in secretory cells (分泌细胞, e.g. pancreas), SER abundant in detox cells (解毒细胞, e.g. liver)
- Protein content 蛋白差异: e.g. reticulons enriched in SER, not in RER
5. Ribosome Locations and Functions 核糖体的位置与功能
- Free ribosomes (自由核糖体)
- EN: Float in cytosol, make proteins that stay inside the cell.
- CN: 游离在胞质中，合成留在细胞内部的蛋白。
- RER-bound ribosomes (附着在RER上的核糖体)
- EN: Translate proteins into the ER lumen for secretion, membrane insertion, or lysosomal targeting.
- CN: 将蛋白质翻译进入ER腔，供分泌、膜嵌入或进入溶酶体。
Co-Translation Process on ER 内质网上的共翻译过程
Initiation 起始
- EN: Free ribosomes meet an mRNA with a signal sequence and start translation. The signal peptide is the first part to be translated.
- CN: 游离核糖体与带有信号序列的 mRNA 结合并开始翻译。最先翻译出来的是信号肽。
Signal Recognition 信号识别
- EN: The signal peptide may be at the N-terminal or as an internal signal peptide (which also functions as a start-transfer signal).
- CN: 信号肽可以位于 N 端，也可以是一个内部信号肽（同时作为起始转运信号）。
- EN: Either way, it is recognized by SRP (Signal Recognition Particle). SRP binds to the peptide, pauses translation, and guides the ribosome–mRNA–peptide complex to the ER. SRP then binds the SRP receptor on the ER membrane. Both hydrolyze GTP, release energy, and SRP is released.
- CN: 无论哪种情况，信号肽都会被 **SRP（信号识别颗粒）**识别。SRP 与肽结合，使翻译暂停，并引导核糖体–mRNA–肽复合物到达内质网。随后 SRP 与 ER 上的 SRP 受体结合，双方水解 GTP，释放能量，SRP 被释放。
Docking to Translocon 锚定到易位子
- EN: The ribosome docks onto the translocon on the ER membrane. The signal peptide inserts into the translocon and opens the pore.
- CN: 核糖体停靠在 ER 膜上的 易位子（translocon），信号肽插入其中并打开通道。
Co-Translation 共翻译过程
- EN: Translation resumes. The growing polypeptide either:
- Inserts into the ER membrane if it is a membrane protein, or
- Passes into the ER lumen if it is a soluble/secreted protein.
- CN: 翻译继续进行。新生多肽链会：
- 如果是膜蛋白，则插入 ER 膜；
- 如果是可溶性或分泌蛋白，则进入 ER 腔。
Membrane Protein Insertion 膜蛋白的插入
- EN: For membrane proteins, the internal signal peptide acts as a start-transfer signal, initiating insertion. When a stop-transfer signal appears, threading stops.
- One start- and stop-transfer pair = single-pass membrane protein
- Several start/stop pairs = multi-pass membrane protein
- CN: 对于膜蛋白，内部信号肽作为起始转运信号，触发插入。当翻译出 停转运信号（stop-transfer signal） 时，蛋白穿膜过程停止。
- 一组起始/停止信号 → 单次跨膜蛋白
- 多组起始/停止信号 → 多次跨膜蛋白
Soluble/Secreted Proteins 可溶性/分泌蛋白
- EN: When soluble or secreted proteins enter the ER lumen, signal peptidase cleaves off the N-terminal signal peptide. The remaining part becomes the mature protein.
- CN: 可溶性或分泌蛋白进入 ER 腔后，**信号肽酶（signal peptidase）**会切除 N 端的信号肽，其余部分作为**成熟蛋白**留在腔内。
Folding and Glycosylation 折叠与糖基化
- EN: Proteins undergo folding and glycosylation (which occurs only inside the ER lumen). The ER also performs quality control—misfolded or incorrectly modified proteins are sent back to refold.
- CN: 蛋白质在 ER 腔内完成折叠与糖基化（糖基化仅发生在 ER 腔）。ER 还会进行质量控制——错误折叠或修饰不当的蛋白会被送回重新处理。
Transport to Golgi 转运至高尔基体
- EN: After correct processing, proteins are packed into vesicles and transported to the Golgi apparatus.
- CN: 完成修饰后，蛋白被装入囊泡并运输到 高尔基体。
Final Destinations 最终去向
- EN: These proteins may:
- Be secreted outside the cell,
- Become plasma membrane proteins,
- Enter endosomal compartments (e.g., lysosomes),
- Or stay in the lumen of endosomal/lysosomal organelles.
- CN: 这些蛋白的最终去向可能是：
- 分泌到细胞外，
- 成为质膜蛋白，
- 进入内体或溶酶体等区室，
- 或留在这些区室的腔内。
🧬 After Co-Translation into ER: What Happens Next?
Once the nascent protein has entered the lumen of the ER, a tightly regulated series of folding, post-translational modifications, and quality control (QC) processes occur.
1. Protein Folding and Chaperones
- BiP (Binding immunoglobulin Protein)
A member of the Hsp70 family, BiP binds to hydrophobic regions of nascent polypeptides to prevent aggregation and assist in proper folding.
中文：BiP 是ER腔内最主要的分子伴侣，识别暴露的疏水区域，帮助蛋白正确折叠。 - Calnexin & Calreticulin
These are lectin chaperones that bind to glycoproteins with monoglucosylated N-linked glycans, assisting folding in a sugar-dependent way.
中文：这两个伴侣专门负责带有特定糖结构（N-连接寡糖）的蛋白折叠，属于钙结合分子伴侣。
2. Post-Translational Modifications
- Disulfide bond formation
- Enzyme: Protein Disulfide Isomerase (PDI)
Catalyzes formation and rearrangement of disulfide bonds to stabilize protein structure.
中文：PDI帮助形成/修正二硫键，保障蛋白空间结构稳定。
- Enzyme: Protein Disulfide Isomerase (PDI)
- N-linked glycosylation
- Enzyme: Oligosaccharyltransferase (OST)
Transfers a preassembled oligosaccharide onto Asn residues within the consensus sequence Asn-X-Ser/Thr.
中文：OST把完整的寡糖链转移到蛋白质的天冬酰胺（Asn）上。
- Enzyme: Oligosaccharyltransferase (OST)
- GPI-anchor addition (optional for some proteins)
Proteins destined for the plasma membrane may receive a GPI-anchor for anchoring to the outer leaflet.
中文：某些膜蛋白会在ER被换成GPI锚，方便之后插入细胞膜外侧。
3. Quality Control and Degradation Pathways
If folding fails or is delayed, the protein is triaged by three major ER Quality Control systems, often referred to as:
✅ A. ER Quality Control (ERQC)
- Involves: Calnexin/Calreticulin cycle
- Misfolded glycoproteins are reglucosylated by UGGT (UDP-glucose:glycoprotein glucosyltransferase) to re-enter the chaperone cycle.
中文：UGGT能识别未折叠好的蛋白并重新加糖，让其再进一次Calnexin/Calreticulin循环，尝试再次折叠。
🚨 B. ER-associated degradation (ERAD)
- Terminally misfolded proteins are retrotranslocated to the cytosol via a dislocon complex (e.g., Derlin-1, Hrd1, and p97 ATPase).
- Once in the cytosol, they are ubiquitinated and degraded by the proteasome.
中文：严重折叠失败的蛋白通过Derlin/Hrd1复合物被“打包送出”ER，并被泛素标记，送去细胞质内的蛋白酶体降解。
🔥 C. Unfolded Protein Response (UPR)
- If misfolded proteins accumulate, the ER stress triggers UPR via:
- IRE1 → splices XBP1 mRNA → transcription of chaperones
- PERK → phosphorylates eIF2α → slows translation
- ATF6 → cleaved in Golgi → activates ER stress genes
中文：UPR是一种“全局应急反应”，包括减少翻译、增加伴侣蛋白、扩大ER等。三个关键感受器：IRE1、PERK 和 ATF6。
🔁 Summary Table
| Step | Key Molecules | Function | 中文解释 |
|---|---|---|---|
| Folding | BiP, Calnexin, Calreticulin | Assist protein folding | 协助蛋白质折叠 |
| Disulfide bonds | PDI | Stabilize structure | 形成二硫键 |
| Glycosylation | OST | N-linked sugar addition | N-连接糖基化 |
| QC cycle | UGGT, Calnexin | Retry folding | 检测/再折叠 |
| Degradation | Derlin-1, Hrd1, p97 | Send to proteasome | ERAD通路 |
| Stress response | IRE1, PERK, ATF6 | Activate UPR | 激活未折叠蛋白反应 |