"Newly synthesized proteins exit the endoplasmic reticulum (ER) via coat protein complex II (COPII) vesicles. Procollagen (PC), however, forms prefibrils that are too large to fit into typical COPII vesicles; PC thus needs large transport carriers, which we term megacarriers. TANGO1 assists PC packing. TANGO1 recruited Sedlin[TRAPPC2], a TRAPP component that is defective in spondyloepiphyseal dysplasia tarda (SEDT)[short stature disorder], and that Sedlin was required for the ER export of PC. Sedlin bound and promoted efficient cycling of Sar1, a guanosine triphosphatase that can constrict membranes, and thus allowed nascent carriers to grow and incorporate PC prefibrils. This joint action of TANGO1 and Sedlin sustained the ER export of PC, and its derangement may explain the defective chondrogenesis underlying SEDT."
So could increasing Sedlin levels increase height by enhancing the ER export of procollagen?
LSJL downregulates TRAPPC3 and TRAPPC4.
"Spondyloepiphyseal dysplasia tarda (SEDT) is an X-linked skeletal disorder characterized by short stature, a short trunk, and precocious osteoarthritis. SEDT is caused by mutations in the gene SEDL"
"PCII transport was impaired by Sedlin depletion, with a marked inhibition of its ER exit and extracellular secretion"
"Selective impairment of the ER exit of PC was induced by depleting the whole TRAPP by knockdown of Bet3 (TRAPPC3), a core component of the complex that, when depleted, destabilizes TRAPP"<-So it may be bad that LSJL downregulates TRAPPC3.
"Sar1 was more stably associated with membranes in Sedlin-depleted cells relative to control cells "
"TANGO1 overexpression increased Sedlin association with ERES and also accelerated the ER exit of PC"
"Slower COPII cycles and increased Sar1-GTP levels similar to those caused by Sedlin depletion were detected in Bet3/TRAPP-depleted cells, indicating that Sedlin acts to control the active state of Sar1 as a TRAPP component."
"Sedlin binds Sar1. Bet3 binds Sec23, but only after Sar1 has been released from membranes and vesicles have detached from ER membranes. The Sedlin-Sar1 interaction precedes release of COPII vesicles and accelerates dissociation of Sar1 from membranes, thus allowing the next layer of interaction between COPII and TRAPP. TRAPP would then play a role in subsequent events such as Rab1 activation, thereby exhibiting the unique property of coupling the cycles of Sar1 and Rab1, two GTPases acting in series in ER-to-Golgi transport."
TRAPPC4 may be involved in ERK1/2 phosphorylation according to TRAPPC4-ERK2 interaction activates ERK1/2, modulates its nuclear localization and regulates proliferation and apoptosis of colorectal cancer cells. "Depletion of TRAPPC4 inhibited cell growth and induced apoptosis, while its overexpression contributed to cell growth"
The decrease in TRAPPC3 and TRAPPC4 may be part of the adaptative response due to TRAPCC reducing procollagen release from the ER and finding ways to increase to the TRAPPC's may be a way to increase height via LSJL or otherwise. Also, finding a Sar1 inhibitor may be a method as well.
"SEDT (spondyloepiphyseal dysplasia tarda) is a late-onset X-linked recessive skeletal dysplasia caused by mutations in the gene SEDL coding for sedlin. We investigated four missense mutations observed in SEDT and compare biochemical and cellular characteristics relative to the wild-type protein to address the mechanism of disease and to gain insight into the function of the sedlin protein. In mouse growth plates sedlin [is] predominantly expressed in proliferating and hypertrophic chondrocytes. The wild-type protein localized predominantly in the vicinity of the nucleus and the Golgi, with further localization around the cytoplasm, whereas mutation resulted in mislocalization. The D47Y mutant was expressed similarly to the wild-type, but the S73L, F83S and V130D mutants showed particularly low levels of expression that were rescued in the presence of the proteasome inhibitor MG132 (benzyloxycarbonyl-leucylleucylleucinal)[MG132 does other stuff too which is why it may not be an ideal TRAPP stimulating supplement]. Whereas the D47Y mutant folded similarly and had similar stability to the wild-type sedlin as shown by CD and fluorescence, the S73L, F83S and V130D mutants all misfolded during expression. Two independent assays showed that the D47Y mutation resulted in an increased affinity for the transport protein particle component Bet3 compared with the wild-type sedlin. Our results suggest that the sedlin mutations S73L, F83S and V130D cause SEDT by sedlin misfolding, whereas the D47Y mutation may influence normal TRAPP (transport protein particle) dynamics."
"Sedl is expressed predominantly in chondroctyes at various stages of differentiation, including proliferating, prehypertrophic and hypertrophic chondrocytes in the distal femoral joint growth plate "
Sar1 translocation onto the ER-membrane for vesicle budding has different pathways for promotion and suppression of ER-to-Golgi transport mediated through H89-sensitive kinase and ER-resident G protein.
"ER-to-Golgi protein transport involves transport vesicles of which formation is initiated by assembly of Sar1. The assembly of Sar1 is suppressed by protein kinase inhibitor H89, suggesting that ER-to-Golgi transport is regulated progressively by H89 sensitive kinase. ER-resident G(i2) protein suppresses vesicle formation with inhibition of Sar1 assembly. This study examined whether these promotion and suppression of vesicle transport share the same signal pathway, by examining the effects of G(i/o) protein activator mastoparan 7 (Mp-7) and H89 on Sar1 and Sec23 recruitment onto microsomes. In a cell-free system for Sar1 translocation assay, GTPγS addition induced the translocation of Sar1 onto microsomes. Mp-7 and H89 decreased the Sar1 translocation. Double treatment of Mp-7 and H89 strongly decreased Sar1 translocation. In single and double treatments, however, G(i/o) protein inactivator pertussis toxin (IAP) partially restored the suppressive effect of Mp-7, but had not any effect on H89-induced effect. Then, the assembly of Sec23 onto the microsome was also increased by the addition of GTPγS. Sec23 translocation was decreased by Mp-7 and/or H89 treatment and recovered by IAP pretreatment except for H89 single treatment, similarly to Sar1 translocation in each treatment. Inhibitory effects of H89 and Mp-7on ER-to-Golgi vesicle transport by H89 or Mp-7 were also confirmed in a cell culture system by BFA-dispersion and BFA-reconstruction experiments."
"H89 almost completely inhibited phosphorylation of β-tubulin accompanied with slight but significant increase of microsome-coupling β-tubulin and significant decrease of Sar1 assembly, tubulin polymerization and de-polymerization by paclitaxel and nocodazole did not induce any changes in Sar1 assembly onto the microsome. Therefore, these findings that decreased phosphorylation of microsome-coupling tubulin by H89 imply that tubulin phosphorylation is involved in the coupling to the microsome membrane, but not in incorporation into microtubules. For tubulin phosphorylation, Mp-7 had no effect on the phosphorylation of β-tubulin coupled to ER-membrane"
So a Sar1 inhibitor would not work as we want to increase Sec23 translocation to grow taller not decrease it.