Let's talk about Secs: Sec61, Sec62 and Sec63 in signal transduction, oncology and personalized medicine

Abstract

The heterotrimeric Sec61 complex and the dimeric Sec62/Sec63 complex are located in the membrane of the human endoplasmic reticulum (ER) and play a central role in translocation of nascent and newly synthesized precursor polypeptides into the ER. This process involves targeting of the precursors to the membrane and opening of the polypeptide conducting Sec61 channel for translocation. Apart from this central role in the intracellular transport of polypeptides, several studies of the last decade uncovered additional functions of Sec proteins in intracellular signaling: Sec62 can induce ER-phagy in the process of recovery of cells from ER stress and the Sec61 channel can also act as a passive ER calcium leak channel. Furthermore, mutations, amplifications and an overexpression of the SEC genes were linked to various diseases including kidney and liver diseases, diabetes and human cancer. Studies of the last decade could not only elucidate the functional role of Sec proteins in the pathogenesis of these diseases, but also demonstrate a relevance of Sec62 as a prognostic and predictive biomarker in head and neck cancer, prostate and lung cancer including a basis for new therapeutic strategies. In this article, we review the current understanding of protein transport across the ER membrane as central function of Sec proteins and further focus on recent studies that gave first insights into the functional role and therapeutic relevance of Sec61, Sec62 and Sec63 in human diseases.

Figure 1

Protein transport across the endoplasmic reticulum membrane. Mechanism of (a) co-translational and (b) posttranslational transport of precursor proteins through the Sec61 channel. (c) Topological domains of Sec61α1/ß/γ, (d) Sec62 and (e) Sec63. We note that (i) Sec63 interacts with Sec62 involving a cluster of negatively charged amino-acid residues near the C terminus of Sec63 and positively charged cluster in the N-terminal domain of Sec62, (ii) Sec62 interacts with the N-terminal domain of Sec61α via its C-terminal domain, (iii) BiP can bind to ER luminal loop 7 of Sec61 α via its substrate-binding domain and mediated by the ATPase domain of BiP and the J-domain in the ER luminal loop of Sec63, (iv) Ca²⁺-CaM can bind to an IQ motif in the N-terminal domain of Sec61α and (v) LC3 can bind to a LIR motif in the C-terminal domain of Sec62. 40S, 40S ribosome subunit; 60S, 60S ribosome subunit; SR, heterodimeric SRP receptor; SRP, signal recognition particle.

Figure 2

Regulation of Ca²⁺ homeostasis at the endoplasmic reticulum membrane and Sec62-mediated autophagy. (a) Regulation of Ca2+ efflux through the Sec61 channel. (b) Sec62-mediated autophagy. The red arrows in a indicate inhibitory effects on the passive Ca²⁺ efflux through the Sec61 channel. 40S, 40S ribosome subunit; 60S, 60S ribosome subunit; CaM, calmodulin; CALR, calreticulin; LC3, 1A/1B-light chain 3; SERCA, sarcoplasmic/endoplasmic reticulum Ca²⁺-ATPase.

Figure 3

Overexpression and mutation of SEC61, SEC62 and SEC63 in human diseases. 40S, 40S ribosome subunit; 60S, 60S ribosome subunit; HCC, hepatocellular carcinoma; HNPCC, hereditary non-polyposis colorectal cancer; HNSCC, head and neck squamous cell carcinoma; NSCLC, non-small-cell lung cancer.

Figure 4

Protein translocation complex as a target of bacterial toxins and small molecule therapeutics. Small molecules are written in italic and black letters; bacterial toxins in italic and green letters. The red arrows indicate inhibitory effects directed against the respective target structure. 40S, 40S ribosome subunit; 60S, 60S ribosome subunit; CaM, calmodulin; SERCA, sarcoplasmic/endoplasmic reticulum Ca²⁺-ATPase.