Extracellular macromolecules (proteins, nucleic acids, carbohydrates, lipids) with or without targeting moieties are taken up into cells by endocytosis and sent for degradation into the lysosomes. There are a few exceptions where some toxins (e.g. Shiga toxin) may take another route, which is called retrograde transport where a fraction of the endocytosed toxin will go from endosomes to the Golgi apparatus and from here released into cytosol (see Kirsten Sandvig literature). Another example is cell-penetrating peptides that may penetrate the plasma membrane or endocytic vesicles before they are sent to the lysosomes. It is difficult to give you a clear answer since you not give any detail about the peptide. But, if it is a large poly-peptide I would guess that most of it will go to the lysosomes and be degraded there. To enhance the uptake you could conjugate it to an antibody or ligand to enhance its uptake, however this depends very much on the cells you want to use. Also, you could release the peptide from the endosomes or lysosomes by photochemical internalization (PCI) a technology established in our lab. Another way could be electro permeabilization.

So direct to your Qs:

Q1: Is it true that any molecule like peptide is taken up by cell is through lysosome only.

A1: No

Q2: So if I need to target any molecule to lysosome and then want it to release into cytosol do it require the targeting molecule?

A2: Not any molecule, but it would be an advantage with a targeting molecule to enhance the uptake.

Q3: What would be the fate of any molecule taken up by lysosome?

A3: This depends on the type of molecule. Macromolecules will normally be degraded. Water (H2O) not…

Hi,

Nice question. The targeting of any protein or peptides to lysosome does require some sort of sequence recognition, which could be moiety or amino acid stretch or recognition can be through changes in post-translational modification of that peptide or protein.

To answer your question that any molecule like peptide is taken up by cell is through lysosome only, is not completely true. Interventions for targeting molecules (not any) to lysosome was performed by many investigators, however, the recovery for the lysosome after targeting, I am not sure because most most molecules undergo degradation once they reach lysosome. Lysosome is a powerful and enzymatic machinery for degrading proteins or peptides.

If you want to gain more insights on lysosome and its functional role, please follow the following professor's work. She has done an amazing work and is the leading scientist in the lysosome/autophagy field.

http://www.einstein.yu.edu/faculty/8784/ana-maria-cuervo/

Thanks and all the best,

Mohan

For lysosome targeting protein should be tagged with mannose 6 phosphate. Normally these targeted proteins were degraded by lysosomal enzymes and the Ph of the lysosome is acidic. Keeping all this in view we have to take further step to target or not

Thank you so much @Mohan Pabba. Nice answer and thanks for the link.

Thanks @Girish Prabhakar Bala. 

But if we need targeting moiety to taget lysosome then why it is said that any molecule or peptide targeted to cell is endocytosed to form phagosome; which further form  phagolysosome and taken up by lysosome?

Extracellular macromolecules (proteins, nucleic acids, carbohydrates, lipids) with or without targeting moieties are taken up into cells by endocytosis and sent for degradation into the lysosomes. There are a few exceptions where some toxins (e.g. Shiga toxin) may take another route, which is called retrograde transport where a fraction of the endocytosed toxin will go from endosomes to the Golgi apparatus and from here released into cytosol (see Kirsten Sandvig literature). Another example is cell-penetrating peptides that may penetrate the plasma membrane or endocytic vesicles before they are sent to the lysosomes. It is difficult to give you a clear answer since you not give any detail about the peptide. But, if it is a large poly-peptide I would guess that most of it will go to the lysosomes and be degraded there. To enhance the uptake you could conjugate it to an antibody or ligand to enhance its uptake, however this depends very much on the cells you want to use. Also, you could release the peptide from the endosomes or lysosomes by photochemical internalization (PCI) a technology established in our lab. Another way could be electro permeabilization.

So direct to your Qs:

Q1: Is it true that any molecule like peptide is taken up by cell is through lysosome only.

A1: No

Q2: So if I need to target any molecule to lysosome and then want it to release into cytosol do it require the targeting molecule?

A2: Not any molecule, but it would be an advantage with a targeting molecule to enhance the uptake.

Q3: What would be the fate of any molecule taken up by lysosome?

A3: This depends on the type of molecule. Macromolecules will normally be degraded. Water (H2O) not…

Thanks @Pal K. Salbo

Thanks for the well explained answer.

To answer part of your question, there are a number of ways something can be internalized into the cell (eg: macropinocytosis, clathrin-mediated or caveolin-mediated endocytosis, dynamin-dependent endocytosis, transduction, etc). We work with peptides and cytotoxicity, and we have seen that different peptides can behave very differently with respect to how them seem to get into cells. Naturally, endo/lysosomal trafficking would be the default pathway, but if your peptide does not come into the cell through endosomes, then it can very well end up in the cytoplasm and then move to an organelle or be sent for degradation by the  proteasome or can move to the autophagy-lysosomal pathway. Check for the specific sequences, which will give you a hint on what kind of internalization pathways it will follow. The best way to check is to try tagging your peptide with a fluorescent label or a tag that has an antibody, so you can how it seems to be coming into the cell and where it's going over time.

Keep in mind the lysosome can degrade almost all biological molecules, so your peptide may not stay in-tact after it enters the lysosome. However, it might not be degraded and instead released into the cytoplasm and later degraded by the proteasome or even sent to be released outside the cell. You'll just have to check what's happening to it.

Thanks @John