News and Views How cells coordinate waste removal through their major proteolytic pathways - PowerPoint Presentation

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News and Views

How cells coordinate waste removal through their major proteolytic pathways - Sascha Martens & Andreas BachmairThe eukaryotic cell uses two complex machineries to degrade unwanted proteins. The first is the ubiquitin–proteasome system and the second is autophagy. A new study contributes to our understanding of how the two systems interconnect to coordinate protein degradation.Rubicon swaps autophagy for LAPKeith B. Boyle & Felix RandowPhagocytic cells engulf their prey into vesicular structures called phagosomes, of which a certain proportion becomes demarcated for enhanced maturation by a process called LC3-associated phagocytosis (LAP). Light has now been shed on the molecular requirements of LAP, establishing a central role for the protein Rubicon in the immune response to Aspergillus fumigatus.Super-resolution links vinculin localization to function in focal adhesions Grégory GiannoneIntegrin-based focal adhesions integrate biochemical and biomechanical signals from the extracellular matrix and the actin cytoskeleton. The combination of three-dimensional super-resolution imaging and loss- or gain-of-function protein mutants now links the nanoscale dynamic localization of proteins to their activation and function within focal adhesions.

How cells coordinate waste removal through their major proteolytic pathways -

Sascha Martens & Andreas BachmairNews and Views

Article

Amino-terminal arginylation targets endoplasmic reticulum chaperone BiP for autophagy through p62 bindingHyunjoo Cha-Molstad,1, n1 Ki Sa Sung,2, 3, n1 Joonsung

Hwang

,

1

,

n1

Kyoung

A. Kim

,

1

,

n1

Ji

Eun

Yu

,

1

,

4

,

Young Dong Yoo

,

2

,

Jun

Min Jang

,

5

,

n2

Dong

Hoon

Han

,

6

,

Michael

Molstad

,

2

,

Jung

Gi

Kim

,

1

,

Yoon

Jee

Lee

,

2

,

Adriana

Zakrzewska

,

3

,

Su-

Hyeon

Kim

,

1

,

Sung

Tae Kim

,

2

,

3

,

Sun

Yong Kim

,

7

,

Hee

Gu

Lee

,

8

,

Nak

Kyun

Soung

,

1

,

Jong

Seog

Ahn

,

9

,

Aaron

Ciechanover

,

2

,

10

,

Bo

Yeon

Kim

1

,

&

Yong Tae Kwon

2

,

11

,

We

show that

ATE1

-encoded

Arg

-transfer RNA transferase (R-transferase) of the N-end rule pathway mediates N-terminal

arginylation

of multiple endoplasmic reticulum (ER)-residing chaperones, leading to their cytosolic

relocalization

and turnover. N-terminal

arginylation

of

BiP

(also known as GRP78), protein

disulphide

isomerase and

calreticulin

is co-induced with autophagy during innate immune responses to cytosolic foreign DNA or

proteasomal

inhibition, associated with increased

ubiquitylation

.

Arginylated

BiP

(R-

BiP

) is induced by and associated with cytosolic misfolded proteins destined for p62 (also known as

sequestosome

 1, SQSTM1) bodies. R-

BiP

binds the

autophagic

adaptor p62 through the interaction of its N-terminal arginine with the p62 ZZ domain. This allosterically induces self-

oligomerization

and aggregation of p62 and increases p62 interaction with LC3, leading to p62 targeting to

autophagosomes

and selective lysosomal co-degradation of R-

BiP

and p62 together with associated cargoes. In this

autophagic

mechanism,

Nt

-arginine functions as a delivery determinant, a

degron

and an activating ligand. Bioinformatics analysis predicts that many ER residents use

arginylation

to regulate non-ER processes.

Article

A conserved mechanism of TOR-dependent RCK-mediated mRNA degradation regulates autophagyGuowu Hu,1, n1 Travis McQuiston,1, n1 Amélie Bernard,2, n1 Yoon-Dong

Park

,

1

,

Jin

Qiu

,

1

,

Ali

Vural

,

3

,

Nannan

Zhang

,

1

,

Scott

R. Waterman

,

1

,

Nathan

H. Blewett

,

4

,

Timothy

G. Myers

,

5

,

Richard

J. Maraia

,

4

,

John H. Kehrl

,

3

,

Gulbu

Uzel

,

1

,

Daniel

J. Klionsky

2

,

&

Peter R. Williamson

1

,

Autophagy

is an essential eukaryotic pathway requiring tight regulation to maintain homeostasis and preclude disease. Using yeast and mammalian cells, we report a conserved mechanism of autophagy regulation by RNA helicase RCK family members in association with the

decapping

enzyme Dcp2. Under nutrient-replete conditions, Dcp2 undergoes TOR-dependent phosphorylation and associates with RCK members to form a complex with autophagy-related (

ATG

) mRNA transcripts, leading to

decapping

, degradation and autophagy suppression. Simultaneous with the induction of

ATG

mRNA synthesis, starvation reverses the process, facilitating

ATG

mRNA accumulation and autophagy induction. This conserved post-transcriptional mechanism modulates fungal virulence and the mammalian

inflammasome

, the latter providing mechanistic insight into autoimmunity reported in a patient with a PIK3CD/p110

δ

gain-of-function mutation. We propose a dynamic model wherein RCK family members, in conjunction with Dcp2, function in controlling

ATG

mRNA stability to govern autophagy, which in turn modulates vital cellular processes affecting inflammation and microbial pathogenesis

.

KJ

KJ

KJ

KJ