hey everyone JJ here welcome to another biochemistry lesson in today's lesson
I'm gonna be talking to you guys about the lysosome and end tor signaling and
more specifically mTOR signaling and the role of the lysosome in mTOR signaling
regulation so just to kind of give you guys a brief background so the lysosome
was first discovered in 1955 by Christian de Duve it was originally
thought to be the cells garbage can so it was just thought to be somewhere
where the cell would just kind of get rid of its waste degrade old damaged
proteins but more recent evidence suggests that in addition to these these
things that the lysosome was always thought to have done it also seems to be
important in sensing the nutrient status of the cell so that brings me to mTOR
which is the mammalian or mechanistic target of rapamycin so that's the fancy
name for mTOR it was just found that it was a target of a chemical known as
rapamycin and it it comes in two complexes one is called mTOR complex one
and its main major component that differs in this complex is the the presence of a
protein component known as Raptor and there's also mTOR complex 2 which has the
protein complex known as RICTOR instead of raptor so mTOR is the master
controller of protein sense synthesis in the cell and for protein synthesis to
occur you need energy and nutrients and indeed mTOR is regulated by energy in
the nutrient status of the cell so even just looking at this now you can see
okay if the lysosome is an important nutrient sensor well then there must be
something or somehow these lysosome and mTOR are connected in some way and in
fact they are so just to kind of quickly go over the schematic of how
this occurs say we've got normal autophagy in the cell in another video I'll be
be talking about autophagy so please check out autophagy in one of my other videos so
so autophagy is just AUTO PHAGY which is just self eating that's kind of the actual
name of this process but it really just means that the cell is degrading
proteins it's it's own intracellular proteins and other intracellular
organelles and other components within the lysosome and it does that by
collecting these components in vesicles that are known as Auto phagosomes and
what it does is it actually delivers the auto phagosomes by a process known as
macroautophagy to the lysosome whereby the autophagosomes fuse with a lysosome
depositing the content such as proteins into the lysosome where lysosomal
proteolytic enzymes known as cathepsins actually degrade this protein into amino
acids now here's where it gets interesting guys amino acids are a
nutrient as we all know so in fact the intra lysosome ol nutrient or inter
lysosome amino acid content will actually regulate mTOR and this is how
how it's done so amino acids in the lysosome actually activate a protein
known as regulator and I mean regulator is composed of several several different
subunits but we won't get into that in this video but just know that amino
acids regulate something known as regulator and there's another protein as
well I didn't mention but it's also important in this process and is known
as vATPase or vacular ATPase so we'll talk about that in another
video but just for now we'll look at regulator so amino acids activate
regulator and regulator will actually activate rag proteins so there are
actually four different types of rag proteins a B C and D
and these these isoforms actually form heterodimers with each other so a and B
will form a heterodimer with either C or D so you could get in a rag a and C
heterodimer or rag in D heterodimer or a rag B and C heterodimer a rag B and D
heterodimer so there are four different possible heterodimers that rag proteins
can can make and and these two proteins are actually a part of something very
important in the lysosome which is LYNUS machinery or lysosome nutrient sensing
machinery so l ly for lysosome and U for nutrient and then s for sensing so light
LYNUS machinery these two proteins are involved in - machinery so that's just
the way the lysosome actually senses and monitors inter lysosome will nutrients
so what will happen guys is that when regular gets activated regulators
actually a GEF and a GEF is just a guanine nucleotide exchange factor and what that
means is regulator will actually gtp load rag heterodimers to activate them
now I'll get into this process a bit more in another video so it's kind of a
complicated process but I'll talk to you guys about in another video but just
realize that regulator is AG f it GTP loads rag heterodimers and it activates
them and what it'll do is it'll actually enable the rag heterodimers to actually
bind to some intra cellular proteins and one of those proteins is in fact mTOR
complex one and now mTOR complex one well and in fact actually migrate to the
lysosomal membrane and bind to rag protein and then once it does that it
becomes activated by a number of things but I won't get into that so much in
detail in this video but just be aware that mTOR complex one it gets it binds
to rag proteins it gets activated it it it gets activated by a couple proteins
one of them is Rheb protein ar e RR h-e-b I'll talk about that in another video
but it it it enables its activation when it's bound to rag at the lysosomal
membrane to other proteins that regulate mTOR complex one activity our AMPK or a
MP activated protein kinase and a KT or otherwise known as protein kinase B now
AMPK is a very important energy sensor of the cell it'll actually be activated
by AMP which means that the cell is actually energy deficient so when it
cell is actually energy deficient NPK will be activated and what will happen
is it'll actually negatively regulate mTOR complex one or inhibited which
makes sense right if the cell doesn't have a lot of energy it doesn't want
it's not going to want to put energy into the process of protein synthesis
it's going to it's going to stop protein synthesis from occurring because protein
synthesis is an energy intensive process now a KT is is somewhat different a KT
is activated by by other things such as insulin and what a KT will actually do
is it will actually activate mTOR complex one so just realize that mTOR
complex one is not only regulated by its binding to the licensable membrane but
it's also regulated by other factors such as NPK and a KT but nevertheless if
mTOR complex one is activated what it'll do is it'll start to activate some of
its downstream targets such as P seventy s6 kinase or P 70 at six K so it will
phosphorylate P 70 s 6k p 70s exhale will then actually phosphorylate the S
six subunit on a ribosome activating the ribosome and we all know that the
ribosome is where proteins are actually made or polypeptide chains are actually
made now for protein synthesis to occur and to work properly there you need
initiation and elongation of the polypeptide strand
now there are other proteins that are involved there are many actually there
are many other proteins involved but a couple important ones one in particular
for initiation is e is for e or eukaryotic initiation factor for e não é
I f4 e along with E is for G will actually activate and promote
polypeptide synthesis initiation so just you want to know that these proteins are
involved in polypeptide synthesis as well now not only are these eukaryotic
initiation factors required but there's also a eukaryotic elongation factors in
one of them is eef2 so eukaryotic the lower case e is for eukaryotic and then
this capital lease or elongation factor - now that as his name suggests promotes
elongation of the polypeptide strand when it's being made now what will
happen is these these proteins the initiation factors in this elongation
factor are actually regulated the gif for E and is binding to air and ends
binding partner a if' for D are actually regulated by for 4EBP1 or eIF4e
binding protein 1 so they're actually negatively regulated
and what will happen is the for ATP one actually binds to ëif 4e which inhibits
eIF4E's ability to bind to EIF4G so it's kind of complicated but just
just know that for ATP one actually inhibits CIF 4 E now eef2 is also
regulated by an upstream kinase called eef2 k or EF 2 kinase which actually
inhibits it so EF 2 K will actually phosphorylate and inhibit eef2 now in
order for mTOR to complete its process in promote protein synthesis it has to
deal with these negative regulators and what it does is because mTOR complex
when up regulates and activates p70S6K P70S6K is actually a negative regulator of
eef2 k so if you if you negatively regulate if you inhibit an inhibitor
then you're going to activate the the protein involved so p70S6k actually
inhibits eef2 k so it actually inhibits eef2 k's ability to inhibit EF 2 which
at which means that eef2 becomes activated I know it's complicated
but that's how it works guys and then the other negative regulator regulator
that mTOR has to deal with is 4EBP1 and what it actually does is it actually
directly phosphorylates 4EBP1 to inhibit 4EBP1 from inhibiting EIF4E
so again because mTOR c 1 inhibits 4EBP1 it actually will end up
activating EIF4E and EIF4G which will enable initiation of polypeptide
synthesis at the ribosome all of which will end up leading to polypeptide
synthesis so that's how the whole process works guys anyways guys that was
a brief lesson on mTOR signaling and the role of the lysosome in mTOR regulation
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