SIL1 explained

Nucleotide exchange factor SIL1 is a protein that in humans is encoded by the SIL1 gene.^{[1] [2] [3] [4]}

This gene encodes a resident endoplasmic reticulum (ER), N-linked glycoprotein with an N-terminal ER targeting sequence, 2 putative N-glycosylation sites, and a C-terminal ER retention signal. This protein functions as a nucleotide exchange factor for another unfolded protein response protein. Mutations in this gene have been associated with Marinesco-Sjogren syndrome. Alternate transcriptional splice variants have been characterized.

Discovery and expression

In the mid-1990s, several laboratories independently discovered Sil1 in three different organisms. A conditional lethality screen was used in the yeast Yarrowia lipolytica to detect cellular components that interacted with the 7S RNA or the signal recognition particle (SRP) during co-translational translocation, which led to the identification of the Sls1p gene. Sls1p is an ER-luminal, 54 kDa protein that contains an N-terminal signal sequence and a C-terminal ER-retention motif.^[5] Sls1p fractionated with the membranous fraction and was shown to interact with the Sec61p translocation apparatus. Sls1p was induced by ER stresses, such as heat shock or inhibition of glycosylation, and its deletion resulted in decreased maturation of secretory proteins. This protein also bound to the ADP-bound form of Kar2p, the yeast homolog of BiP, and stimulated its interaction with Sec63, a DnaJ family member and a translocon component. Disruption of the interaction between Sls1p and Kar2p significantly affected the secretion of a reporter protein, leading the investigators to conclude that Sls1p assisted BiP in the translocation of nascent proteins into the ER lumen. Another group working with Saccharomyces cerevisiae conducted a screen for genes that would suppress the severe growth defect observed in the ΔIre1ΔLhs1 yeast double mutants when overexpressed and named this gene the suppressor of Ire1 and Lhs1 deletion 1 (Sil1). Sil1p was shown to be a homolog of Sls1p, and a combined deletion of Sil1p and Lhs1 (yeast GRP170) proved to be lethal after causing a total block in protein translocation into the ER. Mammalian (human) SIL1 was discovered in a yeast two-hybrid screen aimed at identifying proteins that interacted with a mutant ATPase domain of BiP and was initially named BiP-associated protein (BAP). Sequence analysis revealed that BAP is a mammalian homolog of Sls1p and Sil1p and is similar to the cytosolic HSP70-binding protein, HSPBP1. Biochemical data further demonstrated that BAP also had NEF activity for BiP.

Structure and mechanism of nucleotide exchange

Structural data for yeast Sil1p revealed an elongated, “kidney bean”-like molecular shape that consists of 16 α-helices (A1–A16) and lacks β-sheets. The central helices A3-A14 form the armadillo (ARM)-like repeats (ARM1-ARM4), which are named after those found in β-catenin. Each ARM repeat is composed of three α-helices that pack into a superhelix. A crystal structure of yeast Sil1p complexed with the ADP-bound NBD of Kar2p/BiP revealed that the ARM domain of Sil1p wraps around lobe IIb of BiP’s NBD and makes additional contacts with lobe Ib. This interaction causes lobes Ib and IIb to rotate away from each other, leading to ADP release. Point mutations in the Sil1p-interacting site of Kar2p’s NBD specifically disrupted Sil1p binding but retained Kar2p’s ability to interact with Lhs1/GRP170, the other ER NEF, providing the first indication that their mechanisms of NEF activity were different. Homology mapping and comparisons with the structure of cytosolic HSPBP1 indicated that the region of SIL1 encoded by exons 6 and 9 constitutes major BiP-binding sites, and exon 10 encodes a minor interaction site.

Tissue expression

Although SIL1 is ubiquitously expressed, levels vary widely by tissue. The Human Protein Atlas (www.proteinatlas.org) shows that the expression pattern of SIL1 mirrors that of BiP even more closely than that of GRP170, which is a known UPR target, as is BiP. Perhaps the different expression pattern for GRP170 is due to its dual function as a chaperone and a NEF for BiP. SIL1 expression at a single-cell level has also been determined in a number of tissues, which does not strictly correlate with the secretory capacity of the cell, and tissues displaying the highest relative levels of SIL1 are not necessarily those most affected by loss of its function. This might imply an additional function, which has been demonstrated for Sil1p, or an as yet undiscovered role of SIL1 in certain tissues. Understanding this reason for variation in tissue expression will require further studies.

Interactions

SIL1 has been shown to interact with Binding immunoglobulin protein.

Further reading

• Ichhaporia VP, Kim J, Kavdia K, Vogel P, Horner L, Frase S, Hendershot LM . SIL1, the endoplasmic-reticulum-localized BiP co-chaperone, plays a crucial role in maintaining skeletal muscle proteostasis and physiology . Disease Models & Mechanisms . 11 . 5 . dmm033043 . May 2018 . 29666155 . 5992605 . 10.1242/dmm.033043 .
• Ichhaporia VP, Sanford T, Howes J, Marion TN, Hendershot LM . Sil1, a nucleotide exchange factor for BiP, is not required for antibody assembly or secretion . Molecular Biology of the Cell . 26 . 3 . 420–9 . February 2015 . 25473114 . 4310734 . 10.1091/mbc.E14-09-1392 .
• Keats B, Ott J, Conneally M . Report of the committee on linkage and gene order . Cytogenetics and Cell Genetics . 51 . 1–4 . 459–502 . 1989 . 2791656 . 10.1159/000132805 .
• Clark HF, Gurney AL, Abaya E, Baker K, Baldwin D, Brush J, Chen J, Chow B, Chui C, Crowley C, Currell B, Deuel B, Dowd P, Eaton D, Foster J, Grimaldi C, Gu Q, Hass PE, Heldens S, Huang A, Kim HS, Klimowski L, Jin Y, Johnson S, Lee J, Lewis L, Liao D, Mark M, Robbie E, Sanchez C, Schoenfeld J, Seshagiri S, Simmons L, Singh J, Smith V, Stinson J, Vagts A, Vandlen R, Watanabe C, Wieand D, Woods K, Xie MH, Yansura D, Yi S, Yu G, Yuan J, Zhang M, Zhang Z, Goddard A, Wood WI, Godowski P, Gray A . 6 . The secreted protein discovery initiative (SPDI), a large-scale effort to identify novel human secreted and transmembrane proteins: a bioinformatics assessment . Genome Research . 13 . 10 . 2265–70 . October 2003 . 12975309 . 403697 . 10.1101/gr.1293003 .
• Lagier-Tourenne C, Tranebaerg L, Chaigne D, Gribaa M, Dollfus H, Silvestri G, Bétard C, Warter JM, Koenig M . 6 . Homozygosity mapping of Marinesco-Sjögren syndrome to 5q31 . European Journal of Human Genetics . 11 . 10 . 770–8 . October 2003 . 14512967 . 10.1038/sj.ejhg.5201068 . free .
• Colland F, Jacq X, Trouplin V, Mougin C, Groizeleau C, Hamburger A, Meil A, Wojcik J, Legrain P, Gauthier JM . 6 . Functional proteomics mapping of a human signaling pathway . Genome Research . 14 . 7 . 1324–32 . July 2004 . 15231748 . 442148 . 10.1101/gr.2334104 .
• Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M . 6 . Towards a proteome-scale map of the human protein-protein interaction network . Nature . 437 . 7062 . 1173–8 . October 2005 . 16189514 . 10.1038/nature04209 . 4427026 . 2005Natur.437.1173R .
• Anttonen AK, Mahjneh I, Hämäläinen RH, Lagier-Tourenne C, Kopra O, Waris L, Anttonen M, Joensuu T, Kalimo H, Paetau A, Tranebjaerg L, Chaigne D, Koenig M, Eeg-Olofsson O, Udd B, Somer M, Somer H, Lehesjoki AE . 6 . The gene disrupted in Marinesco-Sjögren syndrome encodes SIL1, an HSPA5 cochaperone . Nature Genetics . 37 . 12 . 1309–11 . December 2005 . 16282978 . 10.1038/ng1677 . 33094308 .
• Otsuki T, Ota T, Nishikawa T, Hayashi K, Suzuki Y, Yamamoto J, Wakamatsu A, Kimura K, Sakamoto K, Hatano N, Kawai Y, Ishii S, Saito K, Kojima S, Sugiyama T, Ono T, Okano K, Yoshikawa Y, Aotsuka S, Sasaki N, Hattori A, Okumura K, Nagai K, Sugano S, Isogai T . 6 . Signal sequence and keyword trap in silico for selection of full-length human cDNAs encoding secretion or membrane proteins from oligo-capped cDNA libraries . DNA Research . 12 . 2 . 117–26 . 2007 . 16303743 . 10.1093/dnares/12.2.117 . free .
• Karim MA, Parsian AJ, Cleves MA, Bracey J, Elsayed MS, Elsobky E, Parsian A . A novel mutation in BAP/SIL1 gene causes Marinesco-Sjögren syndrome in an extended pedigree . Clinical Genetics . 70 . 5 . 420–3 . November 2006 . 17026626 . 10.1111/j.1399-0004.2006.00695.x . 28527790 .

External links

• GeneReviews/NCBI/NIH/UW entry on Marinesco-Sjögren Syndrome

Notes and References

1. Tyson JR, Stirling CJ . LHS1 and SIL1 provide a lumenal function that is essential for protein translocation into the endoplasmic reticulum . The EMBO Journal . 19 . 23 . 6440–52 . December 2000 . 11101517 . 305876 . 10.1093/emboj/19.23.6440 .
2. Chung KT, Shen Y, Hendershot LM . BAP, a mammalian BiP-associated protein, is a nucleotide exchange factor that regulates the ATPase activity of BiP . The Journal of Biological Chemistry . 277 . 49 . 47557–63 . December 2002 . 12356756 . 10.1074/jbc.M208377200 . free .
3. Senderek J, Krieger M, Stendel C, Bergmann C, Moser M, Breitbach-Faller N, Rudnik-Schöneborn S, Blaschek A, Wolf NI, Harting I, North K, Smith J, Muntoni F, Brockington M, Quijano-Roy S, Renault F, Herrmann R, Hendershot LM, Schröder JM, Lochmüller H, Topaloglu H, Voit T, Weis J, Ebinger F, Zerres K . 6 . Mutations in SIL1 cause Marinesco-Sjögren syndrome, a cerebellar ataxia with cataract and myopathy . Nature Genetics . 37 . 12 . 1312–4 . December 2005 . 16282977 . 10.1038/ng1678 . 28860307 .
4. Web site: Entrez Gene: SIL1 SIL1 homolog, endoplasmic reticulum chaperone (S. cerevisiae).
5. Ichhaporia VP, Hendershot LM . Role of the HSP70 Co-Chaperone SIL1 in Health and Disease . International Journal of Molecular Sciences . 22 . 4 . 1564 . February 2021 . 33557244 . 10.3390/ijms22041564 . 7913895 . free .