Chinese scholars published the article Nature to reveal the key to male fertility: an unknown ribosome

According to a mouse study published yesterday (Dec.
14) in the journal Nature, a newly discovered ribosome type appears to play a key role in male reproductive health, synthesizing and neatly and safely folding proteins in sperm in preparation for their arduous journey
.
In the case of a loss of ribosomes (called Ribosome^ST) found by the researchers, male fertility dropped dramatically, and in vitro tests showed that this was because ribosomes packed proteins in a special way that allowed them to last long enough to fertilize
.

"We need more of this basic science to understand the basic biology of sperm," commented Kaitlyn Webster, a reproductive developmental biologist at Harvard Medical School who was not involved in the study, adding that she was intrigued
by the discovery that protein folding plays such an important role in ensuring sperm remain stable for the time they need to be.
"This knowledge will inform research into male infertility, male contraceptives, and overall reproductive health
.
"

Xuejiang Guo, a reproductive biologist at Nanjing Medical University in China, wrote that the idea for the study stemmed from recent reports that eukaryotic ribosomes appear to be heterogeneous
.

Guo and their colleagues started with a simple proteomic assay designed to detect and quantify ribosomal protein heterogeneity
in 9 mouse tissue samples.
The researchers report that they found that certain ribosome proteins are much more prevalent in the testes than elsewhere, suggesting that ribosomes used in germ cells are somehow different from those found elsewhere in the body
.
The team named these sperm-specific ribosomes Ribosome ST to distinguish them from somatic ribosomes, then purified the cell samples from mouse tissues and performed qPCR analysis to confirm that Ribosome^ST was indeed expressed only in germ cells, suggesting that mice have their own gamete-specific protein production factories
.

Ultimately, the researchers used cryo-electron microscopy to determine that Ribosome^ST had a structurally unique exit tunnel through which the newly formed polypeptide chain passed and began to fold into its final shape
.
This could mean that proteins made from these ribosomes have a different shape
than proteins synthesized by ribosomes from other cells, they wrote in the study.

"Our study provides the first evidence that male germline-specific ribosomes have different functions and are not replaceable by core ribosomes," Guo said, adding that when they found structural differences, it showed that they had a new ribosome, which was exciting
.

To better understand the importance of structural differences, the team then created Ribosome^ST knockout mice
.
In males, the core ribosome cannot compensate for this deficiency, so when males who knock out genes are paired with wild-type females, fertility (defined by the number of live births) drops
significantly compared to all-wild-type pairings.
In addition to fertility measurements, Guo explained that the team performed several measurements on male mice and observed decreased sperm count and motility, as well as "smaller testicular size, lower testicles/body weight ratios, and increased head-to-tail ratio of abnormal sperm," which could explain the decline in fertility in animals
.
The team also tested female knockout mice and "found that they had normal fertility and litter numbers," Guo wrote
.

Further experiments on mouse cell lines showed that ribosomes were the only ribosomes capable of properly folding proteins necessary for spermatogenesis, while in knockout mice lacking ribosomes, the same protein was much
less stable when folded by other ribosomes.

"It's a big deal," commented molecular biologist Vassie Ware, who studies ribosomes at Lehigh University but was not involved in the new paper, adding that to her knowledge, no ribosome specifically for spermatogenesis has ever been described to this extent
.
"It's a beautiful piece
.
It provides an important weight to the hypothesis that specialized ribosomes not only exist, but also have important functions in cellular processes
.
”

Webster said: "At this point, we should expect sperm to bring unexpected results
.
Sperm is very different
from any other cell type.
They transfer between bodies, they have heads and tails, they contribute little except for their nuclear load .
.
.
They also have specialized ribosomes, which is not surprising
.
”

"What's really interesting is why the typical ribosome core is not the best choice for male germ cells because of its unique maturation life cycle, long waiting periods and the difficult journey
to fertilization," Webster said.
Historically, it is thought that sperm were largely suppressed
in transcription and translation during this time.
This study adds to the evidence to the contrary and explores the possibility
that regulation of protein folding and stability may explain how sperm survive.
”

However, she is not entirely convinced of the fertility finding, as she said that using the number of live births as a proxy for fertility may not capture the potential impact on women's reproductive health, such as the potential reduction
in the number of immature eggs, the number of follicles, etc.
It's unclear whether the small number of pups born to knockout mice themselves exhibit any developmental or fertility defects
, she said.

Webster and Guo say it remains to be seen whether the study will lead to new ways to
combat male infertility or low human fertility.
While both cite the fact that RPL39L, the ribosomal protein that makes up Ribosome ST, is present in humans^, Webster said some work is needed to determine whether humans have similar concentrations
of teste-specific ribosomal proteins that make up Ribosome^ST 。 Guo added that the team behind the study is currently screening male infertility patients for novel ribosome signs, saying that doing so "could help us understand its contribution to male infertility and also help us understand the pathological mechanisms
underlying sperm formation defects.
" ”

Ware is equally excited
about what the research means for human health.
"If an individual's ribosomal protein sequence is defective, one would think that these results would extrapolate to humans and affect male fertility
," she wrote.
The fact that male infertility may — at least in some cases — be a "ribosome disease," she added, opens up new opportunities
for diagnosis and potential future "long-term treatment.
"